Embryology - User contributions [en-gb]

User:Z5015686

2016-10-28T02:09:50Z

Z5015686: /* Lab Attendance */

{{ANAT2341Student2016}}

== Lab Attendance==

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:34, 5 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:40, 12 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 19 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 26 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 2 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 9 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:33, 16 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:23, 7 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:37, 14 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 21 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:09, 28 October 2016 (AEDT)

==Lab 1 Assessment==

<pubmed> PMC4770082 </pubmed>

Short Summary Of Findings

The results of this paper suggest that human oocyte developmental potential can be predicted by the quality and maturation of the oocyte prior to fertilisation, (at the 2PN, pronucleus phase). The experiential design outlined in the paper involved measuring the mechanical properties of mouse and human zygotes using minimally invasive technologies (such as micropipette aspiration) to determine which were most predictive of viability (viability was defined as embryos that would most likely survive to blastocyst stage of development.) The results showed that individual parameters had limited predictive power on viability, however when considered together there was a greater distinction between viable and non-viable embryos. Through the use of statistical analysis it was found that their method of classification to predict embryo blastocyst formation that was based on these mechanical properties had >90% precision, 95% specificity and 75% sensitivity. Mice received embryos that were predicted to be either viable or non-viable based on their mechanical properties, which positively correlated to the mice who later had live births. The experimenters then investigated firstly whether there was a correlation between the viable and non-viable embryos and their gene expression, and secondly how/why these mechanical parameters correlated with viability. Interestingly they found that non-viable embryos had a reduced/different expression of some genes that are important for processes including, but not limited to, regulating cell cycle, oocyte maturation, chromosome segregation, DNA repair and telomere maintenance, thus suggesting that zygote gene expression correlates with viability. They also found that non-viable oocytes might undergo suboptimal fertilisation. Some genes that were identified to be differentially expressed in viable and non-viable embryos are important for fertilisation, including some whose products are found on the oocyte plasma membrane and in its zona pellucida, where if expressed incorrectly could potentially inhibit sperm-egg binding. Additionally, a reduced expression for a gene coding for a sperm protein was identified in non-viable zygotes, as well as a receptor that is involved in initiating the calcium oscillations that leads to cortical granule release and zona-hardening (which assists in the prevention of polyspermy.) Therefore in conclusion, this research demonstrates a way to accurately predict embryo viability early on in development, at the pronucleus stage, suggesting that embryo developmental potential is determined pre-fertilisation. This research has relevant applications in embryo selection process in IVF clinics.

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of the article's main findings. I guess the question is what provides the zygote viscoelastic properties and sperm gene expression?

| width=100px| Assessment 5/5
|}

==Lab 2 Assessment==

[[File:Rbm24a and rbm24b are expressed throughout somitogenesis.jpeg]]

Rbm24a and rbm24b are expressed throughout somitogenesis<ref><pubmed>25170925</pubmed>
[http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105460 PLOSONE]</ref>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - All information Reference, Copyright and Student Image template correctly included with the file and referenced on your page here.
| Assessment 5/5
|}

==Lab 3 Assessment==

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development.

[[Lecture_-_Ectoderm_Development#Primary_Vesicles|Question 3 - brain vesicles]]
| Assessment 4/5
|}

==Lab 4 Assessment==

===Gastrointestinal Quiz===

<quiz display=simple>

{True/False - Gastrulation, gut formation, is a process that occurs during early embryonic development (week 4), whereby the epiblast layer which derives three germ cell layers (ectoderm, mesoderm and endoderm) is divided into three distinct proportions (the foregut, midgut and hindgut) and through a series of rotations and conformational changes contributes to the formation of different GIT structures (including but not limited to, the liver, stomach, intestines, pancreas and spleen)
| type="()"}
+   True
-   False

{Which of the following germ layer components contribute to gastrointestinal development:
|type="[]"}
+ Endoderm
- Somatic Mesoderm
+ Splanchnic Mesoderm
+ Ectoderm (Neural Crest)
|| (1) The Endoderm contributes to the epithelium and associated glands; (3) the Splanchnic Mesoderm contributes to the mesentery, CT, smooth muscle and blood vessels; and (4) the Neural Crest component of the Ectoderm contributes to the development of the enteric nervous system.

{Which of the following statements is '''incorrect''':
|type="()"}
-   The intraembryonic coelom (lateral plate of the mesoderm) is responsible for the formation of the three major body cavities including the pericardial, pleural and peritoneal (where most of the GIT will eventually lie within)
-   Each gastrointestinal tract division can be defined by the vascular artery supply to each, the Foregut by the celiac artery, the Midgut by the superior mesenteric artery and the Hindgut by the inferior mesenteric artery
+   The buccopharyngeal and cloacal membrane degenerate at the same point in time during gastrointestinal development in a normal healthy embryo
-   During embryonic development most of the gastrointestinal tract undergoes some degree of mechanical rotation
|| The cloacal membrane degenerates later after it fuses with the urogenital septum and forms two distinct regions, an anterior binary and dorsal rectal component.

{Which of the following statements regarding gastrointestinal abnormalities is '''most correct''':
|type="()"}
-   The lumen abnormality of duplication, which is the incomplete recanalisation resulting in parallel lumens, is only found to occur in sites located within/surrounding the stomach region
-   Intestinal malrotation displays no clinical symptoms until later childhood
-   Intestinal Aganglionosis is a condition resulting from reduced migration of neural crest cells, (which are responsible for the development of the enteric nervous system and specifically gastric motility) is most commonly experienced higher up in the gastrointestinal tract (towards the oral cavity)
+   Meckel's Diverticulum is the most common GIT abnormality, with an incidence rate of roughly 1-2% in a population
|| (1) Cases of duplication have been found throughout the GIT, including but not limited to the stomach; (2) Clinical symptoms of Intestinal malrotation are present from birth (i.e. neonatals: bilious vomiting and bloody stools); (3) Intestinal Aganglionosis is typically at the anal end of the GIT, and its severity increases the higher up the GIT.

</quiz>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions, with some minor suggestions for improvement. Question 1 needs an explanation. Question should explain multiple answers are correct. Question 3 has a number of different topics mixed together, not good in MCQs. Question 4 is complicated for most correct type.
| Assessment 5/5
|}

==Lab 5 Assessment==

Completed Course Feedback Questionnaire

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 9 September 2016 (AEST)

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.
| Assessment 5/5
|}

==Lab 6 Assessment==

'''Identify a known genetic mutation that is associated with cleft lip or palate:'''
Mutations in the Interferon Regulatory Factor 6 (IRF6) protein-coding gene (located on chromosome 1) account for the majority of cases of Van der Woude syndrome (VDWS), an autosomal dominant genetic disorder, which has been found to be associated with both cleft lip and cleft palate.

'''Identify a recent research article on this gene:''' PMID 23029012

'''How does this mutation affect developmental signaling in normal development:'''
For the most part the underlying mechanism behind the mutation of the IRF6 gene and the development of cleft lip and palate is largely unknown. However, animal studies involving Irf6 mutant mice have offered an explanation to why this gene could contribute to the development of these abnormalities. These mice presented with hyper-proliferative epidermis failing to undergo terminal differentiation, leading to epithelial adhesions that are able to occlude the oral cavity. IRF6 is also thought to be involved in keratinocyte proliferation and differentiation as well as the formation of the oral periderm. <ref><pubmed>21331089</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/21331089]</ref> Recent research suggests that IRF6 gene interacts with other genes, specifically the Transforming Growth Factor Alpha (TGFA) gene (involved in activating a signalling pathway responsible for cell proliferation, differentiation and development) and may account for up to 10% of cleft lip and cleft palate cases. Interestingly, IRFA knockout mice didn’t express Tgfa in tissues in the palate.
<ref><pubmed>23029012</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/23029012]</ref>
In summary it is thought that mutations in the IRF6 gene are thought to affect developmental signalling directly or through associations with other genes, however more research is required.

{| width=95%
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| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - [http://www.omim.org/entry/607199 OMIM IRF6] is a good example. It would have been good to describe the full signaling pathway in the last part of the answer.
| Assessment 5/5
|}

==Lab 7 Assessment==

'''What is/are the dystrophin mutation(s)?'''
The dystrophin gene is the largest known human gene and is located on locus Xp21. Mutations of this gene (such as selections, point mutations and duplications) affect the structure/function of the protein dystrophin, and is responsible for causing both Duchenne (DMD) and Becker (BMD) muscular dystrophies<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>, which have a prevalence 4.78 and 1.53 per 100,000 males respectively.<ref><pubmed>24780148</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/24780148]</ref>
Although they have similar signs and symptoms, they vary in their severity, onset age and rate at which the disease develops - with DND being in general, the more common and severe of the two, appearing earlier in childhood in the from of muscle weakness and rapidly develops, affected individuals have impaired development of normal motor functions. Both are associated with the heart condition cardiomyopathy (weakened cardiac muscles).<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What is the function of dystrophin?'''
Dystrophin is an important cytoskeletal protein, and is a crucial component of the larger dystrophin-glycoprotein complex (DGC) which functions to both stabilise and signal interactions between the cytoskeleton, membrane and extracellular matrix, essentially have a central role in mediating muscle stability. Dystrophin has four main functional domains (actin binding amino terminal, central rod, cysteine-rich domains and carboxyl terminus) which help mediate the complexes interactions with cellular components, for example mediates interactions with actin filaments through the actin binding domain, and interactions with microtubules through the rod domain.<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What other tissues/organs are affected by this disorder?'''
This disorder is known to result in both cardiac failure and respiratory failure due to the weakening of muscles (as healthy muscle fibres are lost and replaced by fibrosis and fat, and thus have reduced function.)<ref><pubmed>4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What therapies exist for DMD?'''
Diagnosis of DMD can be confirmed through DNA tests, muscle biopsy (testing for presence or relative size of dystrophin) and even prenatal tests, and although there is no current cure for this disease, some treatments are available to help control age of onset in the hope to maximise affected individuals quality of life. Pharmacological treatments include corticosteriods (including prednisolone and deflazacort) which have shown some benefits in patients such as an improvement in strength, pulmonary function, timed motor function and delaying age at loss of ambulation and cardiomyopathy onset - however, these medications are not without their own set of side effects.<ref><pubmed>26833937</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/26833937]</ref> Current research is looking into the possibility gene therapies which aim to restore dystrophin expression such as the use of viral vectors (acting as vehicles for DMD gene)<ref><pubmed>27215286</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/27215286]</ref>, and antisense oligonucleotide mediated exon skipping. <ref><pubmed>23829870</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/23829870]</ref>

'''What animal models are available for muscular dystrophy?'''
Historically the most popular animal model for muscular dystrophy over the years has been the MDX mouse, the results of which have been shown to be promising and now a larger animal model of canine DMD (cDMD) is being used.<ref><pubmed> 25740330</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/25740330]</ref>

http://omim.org/entry/300376

http://omim.org/entry/310200

{| width=95%
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| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - Very good.
| Assessment 5/5
|}

==Lab 8 Assessment==
Absent from lab class due to illness

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This was an in class quiz on urogenital development. Please see me and you can attempt this assessment.
|}

==Lab 9 Assessment==
‘’Critical assessment of group projects’’ [[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 01:04, 7 October 2016 (AEDT)

===Group 1 – Wnt Signalling Pathway===
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be.

Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development.

In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful.

===Group 2 – Notch Signaling Pathway ===
First impressions of Group 2’s page on the notch-signaling pathway are all positive. Subheadings are very well defined. They have chosen to include a brief yet informative introduction on the pathway, a simple table outlining the major scientific developments over the last 100 years, the molecular mechanisms of the pathway, its specific role in embryonic development (which they have further defined as cardiovascular and CNS), role in animal development, abnormalities relating to this pathway and a glossary. I think another positive aspect of this project, is that they have identified additional subheadings for which they are still to do research on; a particularly important one is current areas of research which not many groups have included. Furthermore, additional positive aspects of this project include the addition of images on the canonical notch signaling pathway and its role in cardiovascular development (which both appear also to be appropriately added to the website), which support the text nicely. It might also be useful to find a relevant video to include just to break up some of the text, and help make the page more interactive. It appears this group has widely researched their topic using both primary and review articles, which are all appropriately referenced using in-text citations. All of these aspects help to clearly convey the necessary information to the reader, and fulfill much of the required criteria of this project. In terms of their written information, Group 2 has included really detailed information on its role in embryonic cardiovascular development, as well as identifying some of the major research articles that have lead to these discoveries and a little bit about them (which then the reader if they are interested it can go read thanks to the inclusion of the in-text citations.) They do include a section of the roles of this pathway in animal development, which is really interesting and goes beyond the normal scope of this course.

Some negative aspects of the project include that, as part of the criteria being that the project has an “element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations” perhaps it would be useful to consider including a hand drawn image when researching the non-canonical pathway or transcriptional regulation of notch signaling, or even of some of the receptor/ligands involved in this signaling pathway. Furthermore, on a similar note it may be important to summarise the receptor subtypes involved in the different pathways, their role in embryonic development and abnormalities of the receptor subtype specifically relating to embryonic development in a table or dot point format. Additionally perhaps more information on its role in the CNS (or other systems during embryonic development) even if its not as detailed as cardiovascular, may help to inform the reader of all of its various roles.

In conclusion, it appears that this project is one of the strongest, it has very clear and informative subheadings separating well researched written material, supported by images sourced from the Internet. The main criticisms were just including your own innovative diagrams or explanations, videos to help make it more interactive and table or dot points summarizing the different receptor subtypes involved in each pathway. Following the completion of this, and the subheadings yet to be researched (and glossary) it appears that this project is going to be very successful in informing peers about the said pathway.

===Group 4 – Hedgehog Pathway ===
Positive aspects of this project include that Group 4 appear to have well defined subheadings, which function well to help the reader navigate through the page. The information is appropriately referenced using in-text citations, appearing to be from both primary and review articles. There is a significant amount of research on the mechanisms of the pathway but less of a focus on the role of this pathway in embryonic development, which I think is really important in order to relate it back to what we are leaning in both the lectures and tutorials. I think the inclusion of current research is a very important aspect to include in this project, as it identifies the current direction in which this research is heading. This might be also interesting to link to its clinical significance and abnormalities in the signaling pathway.

However, some negative aspects of the page include the lack of an introduction as this essentially establishes your page. You need to include a brief outline of the signaling pathway, a summary of its role in development and the other aspects of it you are looking to discuss. Furthermore, the inclusion of an image outlining the signaling pathway without any information inducing or explaining it should be corrected. The project appears to be very informative but isn’t very interactive and lacks images. Perhaps sourcing images of results from some of the primary articles, which you have referenced or include videos outlining the signaling pathway, might be a useful addition. It might be a good idea to include a glossary at the bottom of the page to help readers to better understand some of these more difficult terms. Also under the subheading of history, like in some of the other projects, a table could be a useful addition, just summarizing all the scientific advances regarding this pathway since it was first discovered, this helps set up how far we have come and then may be helpful when talking about the direction in which we are heading under current research.

In conclusion, this looks like it’s on its way to being a successful project. In summary though, a greater emphasis on its role in embryonic development and conscious effort to make the page more interactive and engaging for the reader will go a long way.

===Group 5 – T-Box===
First impressions alone it is extremely clear that Group 5 has thoroughly researched this topic have tried hard to include many diagrams and tables to help separate their information up in order to more successfully convey the information across to the reader. Positive aspects of this project include the well-defined subheadings, making the navigation through the page very easy. The introduction is informative and introduces the following subheadings of the project well. The inclusion of what does T-Box mean is also interesting, setting you apart from the other projects. One of the best aspects of the project would have to be the summary table of the main T-box genes, which includes its main expression sites, its function and abnormalities relevant to the specific gene. You have made a note to include a timeline for the history of the T-Box gene, which I think would be successful in summarizing the scientific advances since its discovery, and also help to break up paragraphs of writing. The project appears to be referenced correctly using in-text citations, only query is whether the links to the PMID articles say in the bottom of cardiac and limb development are references or just articles in which you haven’t written on yet and will be referenced appropriately when you do later. The inclusion of a glossary is also a good idea just to help define and explain some of the more difficult terms mentioned.

As for negative aspects of the project, there wasn’t too many. Like for every project, in terms of making it more interactive it might be a good idea to include a YouTube video or animation of the signaling pathway or its role in a specific developmental process, as well as your own hand-drawn image just to fulfill the necessary criteria of this assignment. Furthermore, with some of the smaller images that don’t go the full width of the page, it might be a nice idea to align them to the right as a thumbnail next to their relevant text, so readers see them whilst reading about it. Also remember to make a reference the image you have chosen in your text to emphasise its importance to what you are actually talking about. Although the subheading “good places to look” might just be something for you guys while researching, I think that you could utilize this by including various links with more information on the relevant topics of which you have discussed. This would help to make you page more interactive as well.

This project appears to be extremely well done and is definitely one of the strongest. Most of the criticisms are regarding the formatting of the page and making it more interactive for the reader. All in all this is very well researched project!

===Group 6 – TGF-beta===
You guys have made a good start to the project identifying some important subheadings introducing the TGF-beta signaling pathway, outlining its history, current research and limitations (which may be more appropriately labeled as abnormalities.) However, I do think the structure of these should be revised, what I mean by this is that you should create more levels of headings (as currently all the headings are located under the larger heading of introduction.) Furthermore, it terms of the headings, I think you need to introduce the signaling pathway, then discuss the history of its discovery, then discuss the specific mechanisms behind the pathway, its role in embryonic development (which is a very important aspect in order to relate your project back to what we are learning in the lectures and tutorials), then animal models and abnormalities. You have chosen to include some images which appear to be useful for explaining the signaling pathway, however I think it is important to refer to them in your text, as well as appropriately referencing them with the copyright from the original source (as the larger one is missing this information.)

Some negative aspects of this project are the lack of appropriate references, there are no in-text citations and the identified sources that have been used appear to be websites. Remember that most of the information, if not all should be acquired from primary research articles (supplemented with the occasional review article.) Furthermore, similar to other projects, in order to make your page more engaging you could look into including tables (say for the history or summary of receptor subtypes), more images, YouTube links or animations, or an interactive quiz.

In conclusion it seems that there is still a lot of work to be completed on this page before it is to be submitted, however you have made a successful start. The main criticisms are regarding revisiting the subheadings and including the role of embryonic development as I think this is really critical to the project, as well as adding more information to the page in general. In saying that it appears you guys are heading in the right direction!

==Lab 10 Assessment==
{{Stem Cell Presentations 2016}}

==Lab 12 Assessment==
'''Identify a cited research article:''' PMID 25848746

'''Write a brief summary on the papers findings:'''
The researches in this article acknowledge that the administration of neuregulin-1 (NRG1) has been previously proposed as a method to promote cardiac regeneration, and their experiment specifically looked at the role of NRG1 co-receptor ERBB2 in cardiac regeneration (through implementing both loss and gain of function experimental methods.) They first found that NRG1-induced cardiomyocyte proliferation diminished one week after birth as a result of a reduction in ERBB2, and through knockout studies showed that ERBB2 is required for cardiomyocyte proliferation at embryonic and neonatal stages. They also did a series of experiments activating ERBB2 in cardiomyocytes from mice of different ages. Their experiments as a whole, suggest that (1) ERBB2 is needed for cardiomyocyte proliferation and (2) ERBB2 is able to reactivate postnatal cardiomyocyte proliferation and regenerative potentials. They acknowledge that further research and a deeper understanding of this signalling pathway (as well as others) could lead to major advances in regenerative medicines.

'''Describe how the original research result was used in the review article''' (PMID 26932668):
Broadly speaking, this review article summaries the current knowledge the regulation of cardiomyocyte proliferation during both heart development and regeneration. This research article contributed to this review article by highlighting the role that the regulation of the Nrg1/ErbB2 pathway has in controlling postnatal cardiac growth. It was a basis one of their illustrations (Figure 3) which shows (1) that the transition of cardiomyocytes from hyperplastic to hypertrophic growth (during neonatal periods) is correlated with reductions in NRG1 co-receptor ERBB2, and (2) that in cardiomyocytes constitutively active ERBB2 (caERBB2) expression can extend/reactivate cell division (continued hyperplasic growth) as well as hypertrophic growth, which results in cardiomegaly (which is the abnormal enlargement of the heart.)

==References==
<references/>

[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]
PMID 27486480

2016 Group Project 3

2016-10-27T12:46:06Z

Z5015686: /* Inner ear development */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney Development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

===Inner Ear Development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206

===Autoregulatory Loop Of Induction Between FGF10 And FGF8 ===
FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling And Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Hypospadias'''
|Is a term used to describe a male external genital abnormality resulting from a failure of the fusion of male urogenital folds, it is one of the most common penis abnormalities (1 in 300 births)
|-bgcolor="FAF5FF"
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-bgcolor="FAF5FF"
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-bgcolor="FAF5FF"
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-bgcolor="FAF5FF"
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-bgcolor="FAF5FF"
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-bgcolor="FAF5FF"
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:39:42Z

Z5015686: /* Glossary */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney Development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206

===Autoregulatory Loop Of Induction Between FGF10 And FGF8 ===
FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling And Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Hypospadias'''
|Is a term used to describe a male external genital abnormality resulting from a failure of the fusion of male urogenital folds, it is one of the most common penis abnormalities (1 in 300 births)
|-bgcolor="FAF5FF"
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-bgcolor="FAF5FF"
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-bgcolor="FAF5FF"
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-bgcolor="FAF5FF"
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-bgcolor="FAF5FF"
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-bgcolor="FAF5FF"
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:33:54Z

Z5015686: /* Kidney development */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney Development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206

===Autoregulatory Loop Of Induction Between FGF10 And FGF8 ===
FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling And Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-bgcolor="FAF5FF"
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-bgcolor="FAF5FF"
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-bgcolor="FAF5FF"
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-bgcolor="FAF5FF"
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:29:33Z

Z5015686: /* Further Information Regarding FGFR Signalling and Embryology */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206

===Autoregulatory Loop Of Induction Between FGF10 And FGF8 ===
FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling And Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-bgcolor="FAF5FF"
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-bgcolor="FAF5FF"
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-bgcolor="FAF5FF"
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-bgcolor="FAF5FF"
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:25:10Z

Z5015686: /* New and emerging research surrounding FGFRs */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206

===Autoregulatory Loop Of Induction Between FGF10 And FGF8 ===
FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-bgcolor="FAF5FF"
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-bgcolor="FAF5FF"
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-bgcolor="FAF5FF"
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-bgcolor="FAF5FF"
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:13:19Z

Z5015686: /* Quiz: How much do you really know about FGF? Take the quiz and find out! */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type?
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electrically coupled receptor
- None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following statements are true?
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which of the following statements are correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 

FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-bgcolor="FAF5FF"
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-bgcolor="FAF5FF"
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-bgcolor="FAF5FF"
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-bgcolor="FAF5FF"
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T12:02:17Z

Z5015686: /* Glossary */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
- Tyrosine kinase receptor
- Electrically coupled receptor
+ None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?.
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which statement is correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 

FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Animal Models'''
|Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
|-
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-bgcolor="FAF5FF"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-bgcolor="FAF5FF"
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-bgcolor="FAF5FF"
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-bgcolor="FAF5FF"
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-bgcolor="FAF5FF"
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-bgcolor="FAF5FF"
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-bgcolor="FAF5FF"
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-bgcolor="FAF5FF"
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T11:54:56Z

Z5015686:

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===
Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ How many FGFRs have been discussed in this page?
|type="()"}
- 1
+ 4
- 18
- 22
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option B is the correct answer.

{ Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
- Tyrosine kinase receptor
- Electrically coupled receptor
+ None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ Which of the following statements regarding FGFR3 is true?.
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?
|type="()"}
+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3
|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which statement is correct?
|type="()"}
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth
|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
|type="()"}
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed
||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 

FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor <ref><pubmed>9435295</pubmed></ref>. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated<ref><pubmed>11290326</pubmed></ref>. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-bgcolor="FAF5FF"
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-bgcolor="FAF5FF"
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-bgcolor="FAF5FF"
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-bgcolor="FAF5FF"
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-bgcolor="FAF5FF"
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-bgcolor="FAF5FF"
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-bgcolor="FAF5FF"
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-bgcolor="FAF5FF"
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-bgcolor="FAF5FF"
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T11:22:42Z

Z5015686: /* Glossary */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ Which of the following statements regarding FGFR3 is true?.
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
- Tyrosine kinase receptor
- Electrically coupled receptor
+ None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ How many FGFRs have been discussed in this page?

|type="()"}
- 1
- 2
- 3
+ 4
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option D is the correct answer.

{ Which of the following molecules will directly bind to the DNA in the final stages of the signal transduction pathway?

|type="()"}

+ATF2 and Elk1
-FAS2 and Raf1
-PLD and Rac1
-PKC and IP3

|| Signalling molecules which bind the DNA molecule are capable of altering gene expression within the cell. In the process of FGFR signalling, the two molecules which do this are ATF2 and Elk1, thus the correct answer is A.

{Which statement is correct?
-The use of an anti-FGFR3 antibody for treatment in skeletal-related disorders has no risk of side-effects or toxicity
+ Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote enlargement of the spinal canal
- Genetic activation of ERK1 only can cause apoptosis of cells within the spinal canal
-ERK1 has been proven to inhibit the formation of chondrocytes in the process of bone growth

|| In a study, it was revealed that when ERK1 and ERK2 in chondrocytes are inactivated, this can promote the enlargement of the spinal canal as well as promote the process by which bone develops. Thus the correct answer is B

{ Regarding lung small cell cancer, one which is very aggressive, abnormalities in FGF signalling have been demonstrated in the pathogenesis of this disease. In the process:
-FGF2 is underexpressed
-FGFR1 is reduced significantly
+FGF2 is over expressed
-FGF9 is over expressed

||Lung small cell cancer is a type of cancer that has the ability to metastasise at very early stages which is why it is considered to be deadly. In studies discussed in the above table which links FGF abnormalities to disease, it has been revealed that over expression of FGF2 is an event that occurs in small cell carcinoma. Thus option C is correct.
</quiz>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.

 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==
Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)
{| class="pretty table"
|-bgcolor="DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Apical Ectodermal Ridge (AER)'''
|Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see [[Musculoskeletal System - Limb Development| Limb Development]]
|-
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-bgcolor="FAF5FF"
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-bgcolor="FAF5FF"
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-bgcolor="FAF5FF"
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-bgcolor="FAF5FF"
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-bgcolor="FAF5FF"
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-bgcolor="FAF5FF"
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesenchymal Tissue'''
|(also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
|-bgcolor="FAF5FF"
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see [[Mesoderm | Mesoderm]]
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-bgcolor="FAF5FF"
|'''Morphogenesis'''
|Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
|-
|'''Phenotype'''
|Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
|-bgcolor="FAF5FF"
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Sensory Placode'''
|Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see [[Lecture - Sensory Development | Sensory Development]]
|-bgcolor="FAF5FF"
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T07:52:19Z

Z5015686: /* Bone Development */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|400px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref> In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.<ref name="PMC4526732"/>

For additional information see the recent (2015) review article by Ornitz1 and Pierre [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ ''Fibroblast growth factor signaling in skeletal development and disease'']

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{ Which of the following statements regarding FGFR3 is true?.
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
|| FGFR3 has many roles ranging from its role in promoting differentiation of prechondrogenic mesenchymal cells to cartilage thus producing chondrocytes to inducing complete growth arrest of cells. This will mean that cell growth will come to a complete hault. Thus option B is correct.

{ Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
- Tyrosine kinase receptor
- Electrically coupled receptor
+ None of the above
|| FGFR are a tyrosine kinase receptor type. Thus meaning, the binding of an extracellular ligand will induce receptor dimerization. This process will allow a tyrosine in the cytoplasmic portion of the receptor to be trans-phosphorylated by its adjacent receptor, which in turn induces a signal through the plasma membrane. Thus option B is the correct.

{ Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Upon observing the illustration of FGFR at the beginning of this page, it is clear that the receptor itself will traverse the lipid bilayer of the cell. Thus option C is correct.

{ How many FGFRs have been discussed in this page?

|type="()"}
- 1
- 2
- 3
+ 4
|| Observing the table of the different types of FGFRs that have been discovered it is clear that there are four types of FGFRs. Thus, option D is the correct answer.

{ How many FGFRs have been discussed in this page?

|type="()"}
||
</quiz>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 

 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T07:19:06Z

Z5015686: /* Bone Development */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref>

In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article<ref name="PMC4526732"/> we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.)

The image also includes FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure).<ref name="PMC4526732"/>

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

File:FGFR receptor subtype.jpeg

2016-10-27T07:09:30Z

Z5015686:

FGFRs are comprised of 3 immunoglobulin domains (IgI-III), with IgIII being the closest to the transmembrane, and IgI being the furthest away. Some features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and that IgIII is a transmembrane (TM) structure with kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specificially binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. This student-drawn image is based upon Figure 1 in the 2005 Review article by Thisse: [https://www.ncbi.nlm.nih.gov/pubmed/16216232 ''Functions and regulations of fibroblast growth factor signaling during embryonic development'']

Z5015686

==Reference==

Image based upon: <pubmed>16216232</pubmed>

[http://www.ncbi.nlm.nih.gov/pubmed/16216232 Developmental Biology] (Direct link to the article that this image is based on)

==Copyright==

Beginning six months after publication, I Kristine (UNSW Student Number z5015686) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

{{Template:Student Image}}

File:FGFR receptor subtype.jpeg

2016-10-27T07:08:49Z

Z5015686:

FGFRs are comprised of 3 immunoglobulin domains (IgI-III), with IgIII being the closest to the transmembrane, and IgI being the furthest away. Some features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and that IgIII is a transmembrane (TM) structure with kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specificially binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. This student-drawn image is based upon Figure 1 in the 2006 Review article by Thisse: [https://www.ncbi.nlm.nih.gov/pubmed/16216232 ''Functions and regulations of fibroblast growth factor signaling during embryonic development'']

Z5015686

==Reference==

Image based upon: <pubmed>16216232</pubmed>

[http://www.ncbi.nlm.nih.gov/pubmed/16216232 Developmental Biology] (Direct link to the article that this image is based on)

==Copyright==

Beginning six months after publication, I Kristine (UNSW Student Number z5015686) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

{{Template:Student Image}}

File:FGFR receptor subtype.jpeg

2016-10-27T06:58:55Z

Z5015686:

FGFRs are comprised of 3 immunoglobulin domains (IgI-III), with IgIII being the closest to the transmembrane, and IgI being the furthest away. Some features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and that IgIII is a transmembrane (TM) structure with kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specificially binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction.

Z5015686

==Reference==

Image based upon: <pubmed>16216232</pubmed>

[http://www.ncbi.nlm.nih.gov/pubmed/16216232 Developmental Biology] (Direct link to the article that this image is based on)

==Copyright==

Beginning six months after publication, I Kristine (UNSW Student Number z5015686) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

{{Template:Student Image}}

File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg

2016-10-27T06:50:42Z

Z5015686: /* Reference */

=FGF and FGFR expression patterns during endochondral and intramembranous bone development=

Fibroblast growth factor (FGF) and FGF receptor (FGFR) expression patterns during endochon- dral bone development. (A–D) Progression of endochondral bone development from the mesenchy- mal condensation to formation of the primary ossifi- cation center. (E) Embryonic growth plate. (F) Postnatal growth plate after formation of the second- ary ossification center. (G) Developmental progres- sion of intramembranous bone development. Cells and tissues are color-coded for expression domains of FGFs and FGFRs. (BM) Bone marrow.

Z5015686

==Reference==

<pubmed>PMC4526732</pubmed>

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/ Genes and Development] (Link to article originally image is sourced from)

==Copyright==
Copyright © 2015 Ornitz and Marie; Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

{{Template:Student Image}}

2016 Group Project 3

2016-10-27T06:45:28Z

Z5015686: /* Bone Development */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. <ref><pubmed>7913883</pubmed></ref>

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article<ref name="PMC4526732"/> FGF2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. <ref><pubmed>21302260</pubmed></ref>

In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone.

The image to the right also includes FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure).

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T06:10:24Z

Z5015686: /* History */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Year'''
|'''Scientific Discovery Regarding FGF/FGFR Signalling'''
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T05:52:55Z

Z5015686: /* FGF and FGFR Abnormalities in Cancer */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref name = "PMID21666749"><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref name = "PMID21666749"/>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name="PMID14614009"><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref name="PMID14614009"/>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 

===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

User:Z5015686

2016-10-27T05:46:12Z

Z5015686:

{{ANAT2341Student2016}}

== Lab Attendance==

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:34, 5 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:40, 12 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 19 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 26 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 2 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 9 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:33, 16 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:23, 7 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:37, 14 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 21 October 2016 (AEDT)

==Lab 1 Assessment==

<pubmed> PMC4770082 </pubmed>

Short Summary Of Findings

The results of this paper suggest that human oocyte developmental potential can be predicted by the quality and maturation of the oocyte prior to fertilisation, (at the 2PN, pronucleus phase). The experiential design outlined in the paper involved measuring the mechanical properties of mouse and human zygotes using minimally invasive technologies (such as micropipette aspiration) to determine which were most predictive of viability (viability was defined as embryos that would most likely survive to blastocyst stage of development.) The results showed that individual parameters had limited predictive power on viability, however when considered together there was a greater distinction between viable and non-viable embryos. Through the use of statistical analysis it was found that their method of classification to predict embryo blastocyst formation that was based on these mechanical properties had >90% precision, 95% specificity and 75% sensitivity. Mice received embryos that were predicted to be either viable or non-viable based on their mechanical properties, which positively correlated to the mice who later had live births. The experimenters then investigated firstly whether there was a correlation between the viable and non-viable embryos and their gene expression, and secondly how/why these mechanical parameters correlated with viability. Interestingly they found that non-viable embryos had a reduced/different expression of some genes that are important for processes including, but not limited to, regulating cell cycle, oocyte maturation, chromosome segregation, DNA repair and telomere maintenance, thus suggesting that zygote gene expression correlates with viability. They also found that non-viable oocytes might undergo suboptimal fertilisation. Some genes that were identified to be differentially expressed in viable and non-viable embryos are important for fertilisation, including some whose products are found on the oocyte plasma membrane and in its zona pellucida, where if expressed incorrectly could potentially inhibit sperm-egg binding. Additionally, a reduced expression for a gene coding for a sperm protein was identified in non-viable zygotes, as well as a receptor that is involved in initiating the calcium oscillations that leads to cortical granule release and zona-hardening (which assists in the prevention of polyspermy.) Therefore in conclusion, this research demonstrates a way to accurately predict embryo viability early on in development, at the pronucleus stage, suggesting that embryo developmental potential is determined pre-fertilisation. This research has relevant applications in embryo selection process in IVF clinics.

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of the article's main findings. I guess the question is what provides the zygote viscoelastic properties and sperm gene expression?

| width=100px| Assessment 5/5
|}

==Lab 2 Assessment==

[[File:Rbm24a and rbm24b are expressed throughout somitogenesis.jpeg]]

Rbm24a and rbm24b are expressed throughout somitogenesis<ref><pubmed>25170925</pubmed>
[http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105460 PLOSONE]</ref>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - All information Reference, Copyright and Student Image template correctly included with the file and referenced on your page here.
| Assessment 5/5
|}

==Lab 3 Assessment==

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development.

[[Lecture_-_Ectoderm_Development#Primary_Vesicles|Question 3 - brain vesicles]]
| Assessment 4/5
|}

==Lab 4 Assessment==

===Gastrointestinal Quiz===

<quiz display=simple>

{True/False - Gastrulation, gut formation, is a process that occurs during early embryonic development (week 4), whereby the epiblast layer which derives three germ cell layers (ectoderm, mesoderm and endoderm) is divided into three distinct proportions (the foregut, midgut and hindgut) and through a series of rotations and conformational changes contributes to the formation of different GIT structures (including but not limited to, the liver, stomach, intestines, pancreas and spleen)
| type="()"}
+   True
-   False

{Which of the following germ layer components contribute to gastrointestinal development:
|type="[]"}
+ Endoderm
- Somatic Mesoderm
+ Splanchnic Mesoderm
+ Ectoderm (Neural Crest)
|| (1) The Endoderm contributes to the epithelium and associated glands; (3) the Splanchnic Mesoderm contributes to the mesentery, CT, smooth muscle and blood vessels; and (4) the Neural Crest component of the Ectoderm contributes to the development of the enteric nervous system.

{Which of the following statements is '''incorrect''':
|type="()"}
-   The intraembryonic coelom (lateral plate of the mesoderm) is responsible for the formation of the three major body cavities including the pericardial, pleural and peritoneal (where most of the GIT will eventually lie within)
-   Each gastrointestinal tract division can be defined by the vascular artery supply to each, the Foregut by the celiac artery, the Midgut by the superior mesenteric artery and the Hindgut by the inferior mesenteric artery
+   The buccopharyngeal and cloacal membrane degenerate at the same point in time during gastrointestinal development in a normal healthy embryo
-   During embryonic development most of the gastrointestinal tract undergoes some degree of mechanical rotation
|| The cloacal membrane degenerates later after it fuses with the urogenital septum and forms two distinct regions, an anterior binary and dorsal rectal component.

{Which of the following statements regarding gastrointestinal abnormalities is '''most correct''':
|type="()"}
-   The lumen abnormality of duplication, which is the incomplete recanalisation resulting in parallel lumens, is only found to occur in sites located within/surrounding the stomach region
-   Intestinal malrotation displays no clinical symptoms until later childhood
-   Intestinal Aganglionosis is a condition resulting from reduced migration of neural crest cells, (which are responsible for the development of the enteric nervous system and specifically gastric motility) is most commonly experienced higher up in the gastrointestinal tract (towards the oral cavity)
+   Meckel's Diverticulum is the most common GIT abnormality, with an incidence rate of roughly 1-2% in a population
|| (1) Cases of duplication have been found throughout the GIT, including but not limited to the stomach; (2) Clinical symptoms of Intestinal malrotation are present from birth (i.e. neonatals: bilious vomiting and bloody stools); (3) Intestinal Aganglionosis is typically at the anal end of the GIT, and its severity increases the higher up the GIT.

</quiz>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions, with some minor suggestions for improvement. Question 1 needs an explanation. Question should explain multiple answers are correct. Question 3 has a number of different topics mixed together, not good in MCQs. Question 4 is complicated for most correct type.
| Assessment 5/5
|}

==Lab 5 Assessment==

Completed Course Feedback Questionnaire

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 9 September 2016 (AEST)

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.
| Assessment 5/5
|}

==Lab 6 Assessment==

'''Identify a known genetic mutation that is associated with cleft lip or palate:'''
Mutations in the Interferon Regulatory Factor 6 (IRF6) protein-coding gene (located on chromosome 1) account for the majority of cases of Van der Woude syndrome (VDWS), an autosomal dominant genetic disorder, which has been found to be associated with both cleft lip and cleft palate.

'''Identify a recent research article on this gene:''' PMID 23029012

'''How does this mutation affect developmental signaling in normal development:'''
For the most part the underlying mechanism behind the mutation of the IRF6 gene and the development of cleft lip and palate is largely unknown. However, animal studies involving Irf6 mutant mice have offered an explanation to why this gene could contribute to the development of these abnormalities. These mice presented with hyper-proliferative epidermis failing to undergo terminal differentiation, leading to epithelial adhesions that are able to occlude the oral cavity. IRF6 is also thought to be involved in keratinocyte proliferation and differentiation as well as the formation of the oral periderm. <ref><pubmed>21331089</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/21331089]</ref> Recent research suggests that IRF6 gene interacts with other genes, specifically the Transforming Growth Factor Alpha (TGFA) gene (involved in activating a signalling pathway responsible for cell proliferation, differentiation and development) and may account for up to 10% of cleft lip and cleft palate cases. Interestingly, IRFA knockout mice didn’t express Tgfa in tissues in the palate.
<ref><pubmed>23029012</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/23029012]</ref>
In summary it is thought that mutations in the IRF6 gene are thought to affect developmental signalling directly or through associations with other genes, however more research is required.

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - [http://www.omim.org/entry/607199 OMIM IRF6] is a good example. It would have been good to describe the full signaling pathway in the last part of the answer.
| Assessment 5/5
|}

==Lab 7 Assessment==

'''What is/are the dystrophin mutation(s)?'''
The dystrophin gene is the largest known human gene and is located on locus Xp21. Mutations of this gene (such as selections, point mutations and duplications) affect the structure/function of the protein dystrophin, and is responsible for causing both Duchenne (DMD) and Becker (BMD) muscular dystrophies<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>, which have a prevalence 4.78 and 1.53 per 100,000 males respectively.<ref><pubmed>24780148</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/24780148]</ref>
Although they have similar signs and symptoms, they vary in their severity, onset age and rate at which the disease develops - with DND being in general, the more common and severe of the two, appearing earlier in childhood in the from of muscle weakness and rapidly develops, affected individuals have impaired development of normal motor functions. Both are associated with the heart condition cardiomyopathy (weakened cardiac muscles).<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What is the function of dystrophin?'''
Dystrophin is an important cytoskeletal protein, and is a crucial component of the larger dystrophin-glycoprotein complex (DGC) which functions to both stabilise and signal interactions between the cytoskeleton, membrane and extracellular matrix, essentially have a central role in mediating muscle stability. Dystrophin has four main functional domains (actin binding amino terminal, central rod, cysteine-rich domains and carboxyl terminus) which help mediate the complexes interactions with cellular components, for example mediates interactions with actin filaments through the actin binding domain, and interactions with microtubules through the rod domain.<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What other tissues/organs are affected by this disorder?'''
This disorder is known to result in both cardiac failure and respiratory failure due to the weakening of muscles (as healthy muscle fibres are lost and replaced by fibrosis and fat, and thus have reduced function.)<ref><pubmed>4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What therapies exist for DMD?'''
Diagnosis of DMD can be confirmed through DNA tests, muscle biopsy (testing for presence or relative size of dystrophin) and even prenatal tests, and although there is no current cure for this disease, some treatments are available to help control age of onset in the hope to maximise affected individuals quality of life. Pharmacological treatments include corticosteriods (including prednisolone and deflazacort) which have shown some benefits in patients such as an improvement in strength, pulmonary function, timed motor function and delaying age at loss of ambulation and cardiomyopathy onset - however, these medications are not without their own set of side effects.<ref><pubmed>26833937</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/26833937]</ref> Current research is looking into the possibility gene therapies which aim to restore dystrophin expression such as the use of viral vectors (acting as vehicles for DMD gene)<ref><pubmed>27215286</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/27215286]</ref>, and antisense oligonucleotide mediated exon skipping. <ref><pubmed>23829870</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/23829870]</ref>

'''What animal models are available for muscular dystrophy?'''
Historically the most popular animal model for muscular dystrophy over the years has been the MDX mouse, the results of which have been shown to be promising and now a larger animal model of canine DMD (cDMD) is being used.<ref><pubmed> 25740330</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/25740330]</ref>

http://omim.org/entry/300376

http://omim.org/entry/310200

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - Very good.
| Assessment 5/5
|}

==Lab 8 Assessment==
Absent from lab class due to illness

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This was an in class quiz on urogenital development. Please see me and you can attempt this assessment.
|}

==Lab 9 Assessment==
‘’Critical assessment of group projects’’ [[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 01:04, 7 October 2016 (AEDT)

===Group 1 – Wnt Signalling Pathway===
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be.

Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development.

In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful.

===Group 2 – Notch Signaling Pathway ===
First impressions of Group 2’s page on the notch-signaling pathway are all positive. Subheadings are very well defined. They have chosen to include a brief yet informative introduction on the pathway, a simple table outlining the major scientific developments over the last 100 years, the molecular mechanisms of the pathway, its specific role in embryonic development (which they have further defined as cardiovascular and CNS), role in animal development, abnormalities relating to this pathway and a glossary. I think another positive aspect of this project, is that they have identified additional subheadings for which they are still to do research on; a particularly important one is current areas of research which not many groups have included. Furthermore, additional positive aspects of this project include the addition of images on the canonical notch signaling pathway and its role in cardiovascular development (which both appear also to be appropriately added to the website), which support the text nicely. It might also be useful to find a relevant video to include just to break up some of the text, and help make the page more interactive. It appears this group has widely researched their topic using both primary and review articles, which are all appropriately referenced using in-text citations. All of these aspects help to clearly convey the necessary information to the reader, and fulfill much of the required criteria of this project. In terms of their written information, Group 2 has included really detailed information on its role in embryonic cardiovascular development, as well as identifying some of the major research articles that have lead to these discoveries and a little bit about them (which then the reader if they are interested it can go read thanks to the inclusion of the in-text citations.) They do include a section of the roles of this pathway in animal development, which is really interesting and goes beyond the normal scope of this course.

Some negative aspects of the project include that, as part of the criteria being that the project has an “element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations” perhaps it would be useful to consider including a hand drawn image when researching the non-canonical pathway or transcriptional regulation of notch signaling, or even of some of the receptor/ligands involved in this signaling pathway. Furthermore, on a similar note it may be important to summarise the receptor subtypes involved in the different pathways, their role in embryonic development and abnormalities of the receptor subtype specifically relating to embryonic development in a table or dot point format. Additionally perhaps more information on its role in the CNS (or other systems during embryonic development) even if its not as detailed as cardiovascular, may help to inform the reader of all of its various roles.

In conclusion, it appears that this project is one of the strongest, it has very clear and informative subheadings separating well researched written material, supported by images sourced from the Internet. The main criticisms were just including your own innovative diagrams or explanations, videos to help make it more interactive and table or dot points summarizing the different receptor subtypes involved in each pathway. Following the completion of this, and the subheadings yet to be researched (and glossary) it appears that this project is going to be very successful in informing peers about the said pathway.

===Group 4 – Hedgehog Pathway ===
Positive aspects of this project include that Group 4 appear to have well defined subheadings, which function well to help the reader navigate through the page. The information is appropriately referenced using in-text citations, appearing to be from both primary and review articles. There is a significant amount of research on the mechanisms of the pathway but less of a focus on the role of this pathway in embryonic development, which I think is really important in order to relate it back to what we are leaning in both the lectures and tutorials. I think the inclusion of current research is a very important aspect to include in this project, as it identifies the current direction in which this research is heading. This might be also interesting to link to its clinical significance and abnormalities in the signaling pathway.

However, some negative aspects of the page include the lack of an introduction as this essentially establishes your page. You need to include a brief outline of the signaling pathway, a summary of its role in development and the other aspects of it you are looking to discuss. Furthermore, the inclusion of an image outlining the signaling pathway without any information inducing or explaining it should be corrected. The project appears to be very informative but isn’t very interactive and lacks images. Perhaps sourcing images of results from some of the primary articles, which you have referenced or include videos outlining the signaling pathway, might be a useful addition. It might be a good idea to include a glossary at the bottom of the page to help readers to better understand some of these more difficult terms. Also under the subheading of history, like in some of the other projects, a table could be a useful addition, just summarizing all the scientific advances regarding this pathway since it was first discovered, this helps set up how far we have come and then may be helpful when talking about the direction in which we are heading under current research.

In conclusion, this looks like it’s on its way to being a successful project. In summary though, a greater emphasis on its role in embryonic development and conscious effort to make the page more interactive and engaging for the reader will go a long way.

===Group 5 – T-Box===
First impressions alone it is extremely clear that Group 5 has thoroughly researched this topic have tried hard to include many diagrams and tables to help separate their information up in order to more successfully convey the information across to the reader. Positive aspects of this project include the well-defined subheadings, making the navigation through the page very easy. The introduction is informative and introduces the following subheadings of the project well. The inclusion of what does T-Box mean is also interesting, setting you apart from the other projects. One of the best aspects of the project would have to be the summary table of the main T-box genes, which includes its main expression sites, its function and abnormalities relevant to the specific gene. You have made a note to include a timeline for the history of the T-Box gene, which I think would be successful in summarizing the scientific advances since its discovery, and also help to break up paragraphs of writing. The project appears to be referenced correctly using in-text citations, only query is whether the links to the PMID articles say in the bottom of cardiac and limb development are references or just articles in which you haven’t written on yet and will be referenced appropriately when you do later. The inclusion of a glossary is also a good idea just to help define and explain some of the more difficult terms mentioned.

As for negative aspects of the project, there wasn’t too many. Like for every project, in terms of making it more interactive it might be a good idea to include a YouTube video or animation of the signaling pathway or its role in a specific developmental process, as well as your own hand-drawn image just to fulfill the necessary criteria of this assignment. Furthermore, with some of the smaller images that don’t go the full width of the page, it might be a nice idea to align them to the right as a thumbnail next to their relevant text, so readers see them whilst reading about it. Also remember to make a reference the image you have chosen in your text to emphasise its importance to what you are actually talking about. Although the subheading “good places to look” might just be something for you guys while researching, I think that you could utilize this by including various links with more information on the relevant topics of which you have discussed. This would help to make you page more interactive as well.

This project appears to be extremely well done and is definitely one of the strongest. Most of the criticisms are regarding the formatting of the page and making it more interactive for the reader. All in all this is very well researched project!

===Group 6 – TGF-beta===
You guys have made a good start to the project identifying some important subheadings introducing the TGF-beta signaling pathway, outlining its history, current research and limitations (which may be more appropriately labeled as abnormalities.) However, I do think the structure of these should be revised, what I mean by this is that you should create more levels of headings (as currently all the headings are located under the larger heading of introduction.) Furthermore, it terms of the headings, I think you need to introduce the signaling pathway, then discuss the history of its discovery, then discuss the specific mechanisms behind the pathway, its role in embryonic development (which is a very important aspect in order to relate your project back to what we are learning in the lectures and tutorials), then animal models and abnormalities. You have chosen to include some images which appear to be useful for explaining the signaling pathway, however I think it is important to refer to them in your text, as well as appropriately referencing them with the copyright from the original source (as the larger one is missing this information.)

Some negative aspects of this project are the lack of appropriate references, there are no in-text citations and the identified sources that have been used appear to be websites. Remember that most of the information, if not all should be acquired from primary research articles (supplemented with the occasional review article.) Furthermore, similar to other projects, in order to make your page more engaging you could look into including tables (say for the history or summary of receptor subtypes), more images, YouTube links or animations, or an interactive quiz.

In conclusion it seems that there is still a lot of work to be completed on this page before it is to be submitted, however you have made a successful start. The main criticisms are regarding revisiting the subheadings and including the role of embryonic development as I think this is really critical to the project, as well as adding more information to the page in general. In saying that it appears you guys are heading in the right direction!

==Lab 10 Assessment==
{{Stem Cell Presentations 2016}}

==Lab 12 Assessment==
'''Identify a cited research article:''' PMID 25848746

'''Write a brief summary on the papers findings:'''
The researches in this article acknowledge that the administration of neuregulin-1 (NRG1) has been previously proposed as a method to promote cardiac regeneration, and their experiment specifically looked at the role of NRG1 co-receptor ERBB2 in cardiac regeneration (through implementing both loss and gain of function experimental methods.) They first found that NRG1-induced cardiomyocyte proliferation diminished one week after birth as a result of a reduction in ERBB2, and through knockout studies showed that ERBB2 is required for cardiomyocyte proliferation at embryonic and neonatal stages. They also did a series of experiments activating ERBB2 in cardiomyocytes from mice of different ages. Their experiments as a whole, suggest that (1) ERBB2 is needed for cardiomyocyte proliferation and (2) ERBB2 is able to reactivate postnatal cardiomyocyte proliferation and regenerative potentials. They acknowledge that further research and a deeper understanding of this signalling pathway (as well as others) could lead to major advances in regenerative medicines.

'''Describe how the original research result was used in the review article''' (PMID 26932668):
Broadly speaking, this review article summaries the current knowledge the regulation of cardiomyocyte proliferation during both heart development and regeneration. This research article contributed to this review article by highlighting the role that the regulation of the Nrg1/ErbB2 pathway has in controlling postnatal cardiac growth. It was a basis one of their illustrations (Figure 3) which shows (1) that the transition of cardiomyocytes from hyperplastic to hypertrophic growth (during neonatal periods) is correlated with reductions in NRG1 co-receptor ERBB2, and (2) that in cardiomyocytes constitutively active ERBB2 (caERBB2) expression can extend/reactivate cell division (continued hyperplasic growth) as well as hypertrophic growth, which results in cardiomegaly (which is the abnormal enlargement of the heart.)

==References==
<references/>

[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]
PMID 27486480

2016 Group Project 3

2016-10-27T05:18:47Z

Z5015686: /* Mouse Models */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref name ="PMID26666435"><pubmed>26666435</pubmed></ref>

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line <ref name="PMID26666435"/>. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T04:43:35Z

Z5015686: /* FGF and FGFR Abnormalities in Cancer */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. <ref><pubmed>26666435</pubmed></ref> The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref>, dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref><pubmed>22309595</pubmed></ref>, FGF17, FGF18 <ref><pubmed>21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T04:09:12Z

Z5015686:

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]
The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.

===Inner ear development===
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. ref><pubmed>26666435</pubmed></ref> The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|-bgcolor="FAF5FF"
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-bgcolor="FAF5FF"
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-bgcolor="FAF5FF"
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-bgcolor="FAF5FF"
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-bgcolor="FAF5FF"
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-bgcolor="FAF5FF"
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The Importance of FGF10 in Limb and Lung Development in Chicks and Mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|-bgcolor="FAF5FF"
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-bgcolor="FAF5FF"
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-bgcolor="FAF5FF"
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-bgcolor="FAF5FF"
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-bgcolor="FAF5FF"
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-bgcolor="FAF5FF"
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==
<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:40:27Z

Z5015686: /* Subtypes of FGFR */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|-bgcolor="FAF5FF"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FAF5FF"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:35:11Z

Z5015686: /* Subtypes of FGFR */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-bgcolor="FFFAFA"
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia (can be severe, with developmental delay and acanthuses)
*Thanatophoric Dysplasia
*Hypochondroplasia
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:27:41Z

Z5015686: /* History */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. <ref><pubmed>26793421</pubmed></ref>

{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:19:40Z

Z5015686: /* History */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant findings of the FGFR signalling pathway over the years. The information is based from information presented in a review article <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
|-bgcolor="FAF5FF"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-bgcolor="FAF5FF"
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-bgcolor="FAF5FF"
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-bgcolor="FAF5FF"
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:12:12Z

Z5015686: /* FGF and FGFR abnormalities in Cancer */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.
(This table is based on information presented in a review article: <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR Abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed>21160078</pubmed></ref> <ref><pubmed>24302556</pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T03:08:40Z

Z5015686: /* FGF and FGFR abnormalities in Cancer */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.
(This table is based on information presented in a review article: <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed>23696246</pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed>20299037</pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed>17255960</pubmed></ref> <ref><pubmed>23175443</pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed>24898159</pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed>10471491</pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed>11953856</pubmed></ref> <ref><pubmed>10023681</pubmed></ref> and FGF10 <ref><pubmed>15208658</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref name = "PMID 23270564"><pubmed>23270564</pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed>11329138</pubmed></ref>, missense mutation in FGFR4 <ref><pubmed>16822847</pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref name = "PMID 23270564"/>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed>8099571</pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed>11325814</pubmed></ref>
*missense mutation in FGFR4 <ref name ="PMID 20844967"><pubmed>20844967</pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref name ="PMID 20844967"/>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed>18362893</pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed>22837387</pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed>15836707</pubmed></ref>, FGF8 <ref><pubmed>21319186</pubmed></ref>, FGF15/19 <ref>pubmed<22309595></pubmed></ref>, FGF17, FGF18 <ref>pubmed<21319186</pubmed></ref>
* over expression of FGFR4 <ref><pubmed>25031272</pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed>9425908</pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed>15307144</pubmed></ref> and FGF9 <ref><pubmed>23867472</pubmed></ref> <ref><pubmed>25413587</pubmed></ref>
*FGFR1 amplification <ref><pubmed>21666749</pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed>21666749</pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed>24302556</pubmed></ref>
*translocation of FGFR3 <ref><pubmed>23661334</pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed><21160078></pubmed></ref> <ref><pubmed><24302556></pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed>11165400</pubmed></ref>
* amplification of FGFR1 <ref name= "PMID 24294370"><pubmed>24294370</pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref name= "PMID 24294370"/>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref name="PMID 24239165"><pubmed>24239165</pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence<ref name="PMID 24239165"/>
|-
| Melanoma <ref><pubmed>8311116</pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed>17538174</pubmed></ref>, overexpression FGF16 <ref><pubmed>24253043</pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed>16822847</pubmed></ref> <ref><pubmed>23344261</pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed>12105858</pubmed></ref>
||
* 2.6-4% <ref><pubmed>23808822</pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed>23243019</pubmed></ref>, FGF6 <ref><pubmed>10945637</pubmed></ref>, FGF8 <ref><pubmed>12778074</pubmed></ref>, FGF10 <ref><pubmed>18068633</pubmed></ref>, FGF15/19 <ref><pubmed>23440425</pubmed></ref>, FGF17 <ref><pubmed>15129425</pubmed></ref>, polymorphism in FGF23 <ref><pubmed>24053368</pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed>14614009</pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed>14614009</pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T02:58:58Z

Z5015686: /* Apert Syndrome */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.
(This table is based on information presented in a review article: <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>26220993</pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed>11390973</pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed><23696246></pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed><20299037></pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed><17255960></pubmed></ref> <ref><pubmed><23175443></pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed><24898159></pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed><10471491></pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed><11953856></pubmed></ref> <ref><pubmed><10023681></pubmed></ref> and FGF10 <ref><pubmed><15208658></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><23270564></pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed><11329138></pubmed></ref>, missense mutation in FGFR4 <ref><pubmed><16822847></pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref><pubmed>< 23270564 ></pubmed></ref>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed><8099571></pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed><11325814></pubmed></ref>
*missense mutation in FGFR4 <ref><pubmed><20844967></pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref><pubmed><20844967></pubmed></ref>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed><18362893></pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed><22837387></pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed><15836707></pubmed></ref>, FGF8 <ref><pubmed><21319186></pubmed></ref>, FGF15/19 <ref><pubmed><22309595></pubmed></ref>, FGF17, FGF18 <ref><pubmed><21319186></pubmed></ref>
* over expression of FGFR4 <ref><pubmed><25031272></pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed><9425908></pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed><15307144></pubmed></ref> and FGF9 <ref><pubmed><23867472></pubmed></ref> <ref><pubmed><25413587></pubmed></ref>
*FGFR1 amplification <ref><pubmed><21666749></pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed><21666749></pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed><24302556></pubmed></ref>
*translocation of FGFR3 <ref><pubmed><23661334></pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed><21160078></pubmed></ref> <ref><pubmed><24302556></pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed><11165400></pubmed></ref>
* amplification of FGFR1 <ref><pubmed><24294370></pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref><pubmed><24294370></pubmed></ref>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref><pubmed><24239165></pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence <ref><pubmed><24239165></pubmed></ref>
|-
| Melanoma <ref><pubmed><8311116></pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed><17538174></pubmed></ref>, overexpression FGF16 <ref><pubmed><24253043></pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed><16822847></pubmed></ref> <ref><pubmed><23344261></pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed><12105858></pubmed></ref>
||
* 2.6-4% <ref><pubmed><23808822></pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed><23243019></pubmed></ref>, FGF6 <ref><pubmed><10945637></pubmed></ref>, FGF8 <ref><pubmed><12778074></pubmed></ref>, FGF10 <ref><pubmed><18068633></pubmed></ref>, FGF15/19 <ref><pubmed><23440425></pubmed></ref>, FGF17 <ref><pubmed><15129425></pubmed></ref>, polymorphism in FGF23 <ref><pubmed><24053368></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><14614009></pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed><14614009></pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T02:47:47Z

Z5015686: /* Animal Models */

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.
(This table is based on information presented in a review article: <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>< 26220993></pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed><11390973></pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed><23696246></pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed><20299037></pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed><17255960></pubmed></ref> <ref><pubmed><23175443></pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed><24898159></pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed><10471491></pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed><11953856></pubmed></ref> <ref><pubmed><10023681></pubmed></ref> and FGF10 <ref><pubmed><15208658></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><23270564></pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed><11329138></pubmed></ref>, missense mutation in FGFR4 <ref><pubmed><16822847></pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref><pubmed>< 23270564 ></pubmed></ref>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed><8099571></pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed><11325814></pubmed></ref>
*missense mutation in FGFR4 <ref><pubmed><20844967></pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref><pubmed><20844967></pubmed></ref>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed><18362893></pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed><22837387></pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed><15836707></pubmed></ref>, FGF8 <ref><pubmed><21319186></pubmed></ref>, FGF15/19 <ref><pubmed><22309595></pubmed></ref>, FGF17, FGF18 <ref><pubmed><21319186></pubmed></ref>
* over expression of FGFR4 <ref><pubmed><25031272></pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed><9425908></pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed><15307144></pubmed></ref> and FGF9 <ref><pubmed><23867472></pubmed></ref> <ref><pubmed><25413587></pubmed></ref>
*FGFR1 amplification <ref><pubmed><21666749></pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed><21666749></pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed><24302556></pubmed></ref>
*translocation of FGFR3 <ref><pubmed><23661334></pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed><21160078></pubmed></ref> <ref><pubmed><24302556></pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed><11165400></pubmed></ref>
* amplification of FGFR1 <ref><pubmed><24294370></pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref><pubmed><24294370></pubmed></ref>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref><pubmed><24239165></pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence <ref><pubmed><24239165></pubmed></ref>
|-
| Melanoma <ref><pubmed><8311116></pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed><17538174></pubmed></ref>, overexpression FGF16 <ref><pubmed><24253043></pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed><16822847></pubmed></ref> <ref><pubmed><23344261></pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed><12105858></pubmed></ref>
||
* 2.6-4% <ref><pubmed><23808822></pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed><23243019></pubmed></ref>, FGF6 <ref><pubmed><10945637></pubmed></ref>, FGF8 <ref><pubmed><12778074></pubmed></ref>, FGF10 <ref><pubmed><18068633></pubmed></ref>, FGF15/19 <ref><pubmed><23440425></pubmed></ref>, FGF17 <ref><pubmed><15129425></pubmed></ref>, polymorphism in FGF23 <ref><pubmed><24053368></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><14614009></pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed><14614009></pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-27T02:41:53Z

Z5015686:

{{ANAT2341Project2016header}}
{{Group Assessment Criteria table}}


=Fibroblast Growth Factor Receptor (FGFR) Pathway=
==Introduction==
The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) <ref name="PMID25772309"><pubmed>25772309</pubmed></ref>

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

===History===
Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.
(This table is based on information presented in a review article: <ref><pubmed>26793421</pubmed></ref>
{| class="pretty table"
| '''1939'''
|The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
|-
|'''1974
|FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
|-
|'''1987'''
| The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
|-
|'''1989'''
| FGF1 and FGF2 were isolated from brain tissue.
|-
|'''1990'''
|FGFR tyrosine kinases were identified for the first time
|-
|'''1991'''
| FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
|-
|'''2005'''
|A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
|-
|'''2013'''
|A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.
|-
|}

=== Overview Of The FGFR Pathway===
23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). <ref name="PMID25772309"/>

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. <ref><pubmed>16216232</pubmed>[http://www.ncbi.nlm.nih.gov/pubmed/16216232]</ref>

[[File:FGFR receptor subtype.jpeg|thumb|none|300px|Simplistic illustration of the FGFR receptors adapted from review article [http://www.ncbi.nlm.nih.gov/pubmed/16216232 Functions and regulations of fibroblast growth factor signaling during embryonic development]]]

===Subtypes of FGFR===
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''FGFR Subtype''' || '''Function''' || '''Abnormalities'''
|- bgcolor="FFFAFA"
|-
| FGFR1 ||
*Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation<ref><pubmed>16207751</pubmed></ref> 
*Involved in formation of the organ of corti and auditory sensory epithelium <ref><pubmed>12194867</pubmed></ref> 
*Expressed in early limb bud <ref><pubmed>1321062</pubmed></ref> 
*Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes<ref><pubmed>17169623 </pubmed></ref> 
*Is a negative regulator of bone growth<ref><pubmed>16815385</pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1)
*Kallmann syndrome
*Osteoglophonic dysplasia
*8p11 myeloproliferative syndrome

|-
| FGFR2 ||
*Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates<ref><pubmed>14723847</pubmed></ref> 
*Acts as a marker of prechondrogenic condensations<ref><pubmed>9784595</pubmed></ref> 
*Expressed in condensing mesenchyme of the early limb bud<ref><pubmed>1315677</pubmed></ref> 
*Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts<ref><pubmed>20489451 </pubmed></ref> 
*Is involved in cranial cell replication or differentiation in both humans and mice.<ref><pubmed>15863034 </pubmed></ref> 
||
*Pfeiffer Syndrome (Type 1-3)
*Apert Syndrome
*Crouzon Syndrome
*Beare-Stevenson cutis gryata syndrome<ref><pubmed>17552943 </pubmed></ref> 
|-
| FGFR3 ||
*Induces complete growth arrest of cells<ref><pubmed>11779141 </pubmed></ref> 
*Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes <ref><pubmed>8432397 </pubmed></ref> 
*Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation<ref><pubmed>8630492 </pubmed></ref> 
*Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed<ref name="PMID 12080084"><pubmed>12080084</pubmed></ref> 
||
*Achondroplasia
*Thanatophoric Dysplasia
*Hypochondroplasia
Severe achondroplasia, with developmental delay and acanthosis
|-
| FGFR4 ||
*Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development<ref name ="PMID 10662638"><pubmed>10662638</pubmed></ref> 
*Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
*It will provide mitogenic and morphogenic signals to regulate normal limb development<ref name="PMID 12080084"/> 
*Promotes intramembranous ossification and participates in the development of calvarial bone<ref name ="PMID 10662638"/> 
||
*Chondrodysplasia
|-
|}

===Signal Transduction===
 [[File:FGF signalling pathway.jpg|thumb|500px|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity<ref><pubmed>1655404</pubmed></ref>. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) <ref><pubmed>11021964</pubmed></ref>.
 
 
In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses <ref><pubmed>1656221</pubmed></ref>.
 
 
With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis <ref><pubmed>9632781</pubmed></ref>.

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining FGF Signalling Pathway
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media>
 
This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.<ref> Oxford University Press (2015, March 9) the FGF Signalling Pathway [Video file]. Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc </ref>
|}

==Role In Embryonic Development==

===Patterning Of The Embryonic Axis===
In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space<ref><pubmed>8575335</pubmed></ref>. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged<ref><pubmed>11389440</pubmed></ref>.

Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

===Limb Bud Formation===
[[File:LIMB BUD.png|200px|thumb|400px|Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle<ref name="PMID25772309"/>]]

Limb buds are structures formed early in [[Lecture - Limb Development| limb development]] which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.<ref><pubmed>9620845</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/9620845]</ref> The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation<ref name="PMID25772309"/> Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8<ref><pubmed>15358670</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/15358670]</ref>) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,<ref name="PMID25772309"/> which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.<ref><pubmed>11101846</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/11101846]</ref><ref><pubmed>12152071</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/12152071]</ref>
FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.<ref><pubmed>25109552</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/25109552]</ref>

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2<ref><pubmed>7908145</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/7908145]</ref>, FGF4<ref><pubmed>8001146</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8001146]</ref> and FGF8<ref><pubmed> 8598907</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/8598907]</ref> induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.<ref name="PMID25772309"/>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining limb bud development
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=VpbdqGJ9LWk</html5media>
 
YouTube video outlining limb bud development<ref>Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk</ref>
|}

===Bone Development===
[[File:FGF and FGFR expression patterns during endochondral and intramembranous bone development.jpeg|thumb|500px|FGF and FGFR expression patterns during endochondral and intramembranous bone development <ref name="PMC4526732"><pubmed>PMC4526732</pubmed>
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526732/]</ref>]]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia.

FGF signalling is involved in both endochondral and intramembranous [[Lecture - Musculoskeletal Development| bone development]], which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are shown in various stages of bone development. Endochondral bone development is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) In comparison, intramembranous bone development is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. <ref name="PMC4526732"/>

TBC

===Kidney development===
The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively <ref><pubmed>18835385</pubmed></ref>. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding<ref><pubmed>10749566</pubmed></ref>. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage <ref name="PMID19272374"><pubmed>19272374</pubmed></ref>. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons<ref name="PMID19272374"/>. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney <ref><pubmed>10594778</pubmed></ref>.
 
 
In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development <ref><pubmed>10691305</pubmed></ref>. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma<ref><pubmed>10385628</pubmed></ref>. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct<ref name="PMID1315677"><pubmed>1315677</pubmed></ref>. In addition, FGFR11 is present in renal vesicles <ref name="PMID1315677"/>.
 
 

===External Genitalia development===
[[File:External genitalia.jpg|thumb|200px|External genitalia development<ref><pubmed>26081573</pubmed></ref>]]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors <ref><pubmed>3723059</pubmed></ref>. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation <ref><pubmed>8896986</pubmed></ref>.
 
 
The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period <ref><pubmed>12004962</pubmed></ref>. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice <ref><pubmed>10021340</pubmed></ref>. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis<ref><pubmed>10804187</pubmed></ref>. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited<ref><pubmed>26081573 </pubmed></ref>.
 
 
 
 


===Inner ear development===
 
[[File:Inner ear development.jpg|500px|thumb|Inner ear development (Image was retrieved from a review article<ref><pubmed>22855724 </pubmed></ref>]]
The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct <ref><pubmed> 12761848</pubmed></ref>. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium<ref><pubmed> 8630492</pubmed></ref>. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea<ref><pubmed> 10474167</pubmed></ref>.
 
 
In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain<ref><pubmed> 8071140</pubmed></ref>. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct <ref><pubmed>8223243</pubmed></ref>. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

==Animal Models==
 
===Mouse Models===
Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.
{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Mouse Type''' || '''Phenotype expressed''' || '''Viability in Null Mutant'''
|- bgcolor="FFFAFA"
|-
| Fgf1-, Fgf21- ||
*impaired energy/lipid metabolism, diabetes under high-fat diet<ref><pubmed>22522926</pubmed></ref> <ref><pubmed>23874946</pubmed></ref> 
||
Viable
|-
| Fgf2- ||
*decreased vascular muscle contractility, low blood pressure, thrombocytosis <ref><pubmed>9461194</pubmed></ref> 
*decreased cardiac hypertrophy in ischaemic injury <ref><pubmed>10491406</pubmed></ref> 
*reduced cortical neurogenesis <ref name="PMID 9576942"><pubmed>9576942</pubmed></ref> 
*reduced skin wound healing <ref name="PMID 9576942"/> 
*reduced trabecular bone formation <ref><pubmed>10772653</pubmed></ref> , dwarfism, rickets, osteomalacia <ref><pubmed>25389287</pubmed></ref> 
||
Viable
|-
| Fgf3- ||
*defective inner ear <ref><pubmed>8223243</pubmed></ref> 
*defective heart <ref name ="PMID21664901"><pubmed>21664901</pubmed></ref> 
||
E15.5 <ref name ="PMID21664901"/> 
|-
| Fgf4- ||
* impaired blastocyst inner cell mass proliferation <ref name="PMID 7809630"><pubmed>7809630</pubmed></ref> 
||
E4-4 <ref name="PMID 7809630"/> 
|-
| Fgf7- ||
* impaired ureteric bud development, decreased number of nephrons <ref name ="PMID 9876183"><pubmed>9876183</pubmed></ref> 
* prone to seizures <ref><pubmed>20505669</pubmed></ref> 
||
Viable <ref name ="PMID 9876183"/> 
|-
| Fgf8- ||
* failed gastrulation <ref><pubmed>10421635</pubmed></ref> 
* defective kidney development <ref><pubmed>16049111</pubmed></ref> 
* defective limb development <ref><pubmed>11101846</pubmed></ref> 
* defective inner ear <ref><pubmed>15741321</pubmed></ref> 
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> 
* defective heart outflow tract <ref><pubmed>14975726</pubmed></ref> 
||
E7 <ref><pubmed>10421635</pubmed></ref> 
|-
| Fgf9- ||
* lung hypoplasia <ref><pubmed>16540513</pubmed></ref> 
* male to female sex reversal <ref><pubmed>11290325</pubmed></ref> 
* rhizomelia <ref><pubmed>17544391</pubmed></ref> 
* shortened small intestine <ref>pubmed<>18653563</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"><pubmed>15621532</pubmed></ref> 
* ataxia <ref><pubmed>19232523</pubmed></ref> 
||
P0 <ref><pubmed>11493531</pubmed></ref> 
||
|-
| Fgf10- ||
* lung hypoplasia <ref name="PMID9784490"><pubmed>9784490</pubmed></ref> 
* defective limb development <ref name="PMID9784490"/> 
* defective inner ear formation <ref><pubmed>14623822</pubmed></ref> 
* defective pancreatic development <ref><pubmed>12810586</pubmed></ref> submandibular salivary gland <ref><pubmed>15972105</pubmed></ref> and defective mammary gland <ref><pubmed>16720875</pubmed></ref> 
* defective tracheal cartilage <ref><pubmed>21148187</pubmed></ref> and cleft palate <ref><pubmed>15199404</pubmed></ref> 
* cecal agenesis <ref><pubmed>22819677</pubmed></ref> 
||
P0 <ref name="PMID9784490"/> 
|-
| Fgf 13- ||
* impaired learning memory and neuronal excitability, neuronal migration defects <ref><pubmed>22726441</pubmed></ref> 
||
Viable
|-
| Fgf14- ||
* impaired learning, memory and neuronal excitability <ref name="PMID 17236779"><pubmed>17236779</pubmed></ref> 
* ataxia <ref><pubmed>12123606</pubmed></ref> and motor weakness <ref name="PMID 17236779"/> 
||
Viable
|-
| Fgf15- ||
* Heart defects in outflow tract <ref><pubmed>15789410</pubmed></ref> 
* neurogenesis <ref><pubmed>18625063</pubmed></ref> 
* bile acid metabolism <ref><pubmed>16213224</pubmed></ref> 
||
E13.5-P7 <ref><pubmed>15789410</pubmed></ref> 
|-
| Fgf16- ||
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable
|-
| Fgf17- ||
* defective cerebellum <ref><pubmed>10751172</pubmed></ref> and frontal cortex <ref><pubmed>17442747</pubmed></ref> 
||
Viable
|-
| Fgf18- ||
* lung development defects <ref name="PMID 15336546"><pubmed>15336546</pubmed></ref> <ref><pubmed>11927601</pubmed></ref> 
* bone and cartilage development defects <ref><pubmed>26595272</pubmed></ref> 
||
P0 <ref name="PMID 15336546"/> 
|-
| Fgf20- ||
* kidney agenesis <ref><pubmed>22698282</pubmed></ref> 
* cardiomyopathy <ref name="PMID 15621532"/> 
||
Viable <ref name="PMID 15621532"/> 
|-
| Fgf23- ||
* deafness, defective middle ear development <ref><pubmed>25243481</pubmed></ref> 
* hyperphosphatemia and impaired vitamin D metabolism <ref name="PMID 14966565"><pubmed>14966565</pubmed></ref> 
||
PW12 <ref name="PMID 14966565"/>
|-
|}

===The importance of FGF10 in limb and lung development in chicks and mice===
[[File:Mice model and limb development.gif|thumb|400px|Mice model and limb development<ref name="PMID9784490"/>]]
In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm<ref><pubmed> 9323126</pubmed></ref>. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme<ref name="PMID4826292"><pubmed> 4826292</pubmed></ref>.
 
 
Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field<ref name="PMID4826292"/>. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity<ref><pubmed> 7889567</pubmed></ref>. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation<ref><pubmed> 8674413</pubmed></ref>.

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis<ref><pubmed> 15632068</pubmed></ref>.In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation<ref name= "PMID9784490"/>.
 

==Abnormalities==
As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

===Achondroplasia===
Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. <ref><pubmed>7913883</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/7913883]</ref> This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).<ref><pubmed>12816345</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/12816345]</ref> As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. <ref><pubmed>8723101</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8723101]</ref>

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. <ref><pubmed>19608863 </pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/19608863]</ref>

===Pfeiffer Syndrome===
Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes.
<ref><pubmed>9300656</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/9300656]</ref><ref name= "PMID25679016"><pubmed>25679016</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/25679016]</ref> This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)<ref name= "PMID25679016"/> Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene.
<ref><pubmed>8434615</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/8434615]</ref><ref><pubmed>10394936</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/10394936]</ref>

{| class="wikitable mw-collapsible mw-collapsed"
! YouTube video outlining Pfeiffer Sydrome
|-
|<html5media height="400" width="533">https://www.youtube.com/watch?v=UKYcDm2QHtU</html5media>
 
YouTube video outlining Pfeiffer Sydrome<ref>wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU</ref>
|}

===Apert Syndrome===
[[File:Syndactyly.jpg|thumb|200px| Syndactyly of the fingers]]
Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. <ref><pubmed>< 26220993></pubmed></ref><ref name= "PMID25679016"/> It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. <ref><pubmed><11390973></pubmed></ref> The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. <ref name= "PMID25679016"/>

===Additional Information Regarding Abnormalities in FGFR Signalling===
The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

{{About OMIM}}
Conditions Mentioned Above:
* [http://omim.org/entry/100800 Achondroplasia]
* [http://omim.org/entry/101600 Pfeiffer Syndrome]
* [http://omim.org/entry/101200 Apert Syndrome]

Fibroblast Growth Factor Receptor Subtypes:
* [http://www.omim.org/entry/136350 Fibroblast Growth Factor Receptor 1]
* [http://www.omim.org/entry/176943 Fibroblast Growth Factor Receptor 2]
* [http://www.omim.org/entry/134934 Fibroblast Growth Factor Receptor 3]
* [http://www.omim.org/entry/134935 Fibroblast Growth Factor Receptor 4]

===FGF and FGFR abnormalities in Cancer===

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers <ref name= "PMID25772309"/>. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. <ref><pubmed><23696246></pubmed></ref>

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.

{| class="pretty table"
|-bgcolor="DDCEF2"
|-
| '''Carcinoma Type''' || '''FGF/FGFRs Associated''' || '''% Affected (if known)'''
|- bgcolor="FFFAFA"
|-
| Bladder ||
*over expression of FGF2 <ref><pubmed><20299037></pubmed></ref>
*amplification, translocation and missense mutation in FGFR3 <ref><pubmed><17255960></pubmed></ref> <ref><pubmed><23175443></pubmed></ref>
||
*FGFR3 was amplified in 3% <ref><pubmed><24898159></pubmed></ref>
*missense mutations in FGFR3 have been observed in 35% <ref><pubmed><10471491></pubmed></ref>
|-
| Breast ||
*amplification of FGF3 and FGF4, over expression of FGF8 <ref><pubmed><11953856></pubmed></ref> <ref><pubmed><10023681></pubmed></ref> and FGF10 <ref><pubmed><15208658></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><23270564></pubmed></ref>, over expression and missense mutation in FGFR3 <ref><pubmed><11329138></pubmed></ref>, missense mutation in FGFR4 <ref><pubmed><16822847></pubmed></ref>
||
*FGFR1 amplification identified in 20% lobular breast cancer <ref><pubmed>< 23270564 ></pubmed></ref>
*FGFR4 amplification found in 10% primary breast tumors <ref><pubmed><8099571></pubmed></ref>
|-
| Colorectal ||
*amplification and missense mutation in FGFR2 and FGFR3 <ref><pubmed><11325814></pubmed></ref>
*missense mutation in FGFR4 <ref><pubmed><20844967></pubmed></ref>
||
*FGFR4 mutation present in 57% of patients <ref><pubmed><20844967></pubmed></ref>
|-
| Glioblastoma ||
* over expression of FGF5 <ref><pubmed><18362893></pubmed></ref>
* over expression and translocation of FGFR1, translocation of FGFR3 <ref><pubmed><22837387></pubmed></ref>
||
* 3.1% exhibit FGFR1 or FGFR3 mutation
|-
| Hepatocellular ||
* over expression of FGF2 <ref><pubmed><15836707></pubmed></ref>, FGF8 <ref><pubmed><21319186></pubmed></ref>, FGF15/19 <ref><pubmed><22309595></pubmed></ref>, FGF17, FGF18 <ref><pubmed><21319186></pubmed></ref>
* over expression of FGFR4 <ref><pubmed><25031272></pubmed></ref>
|-
| Leukemia & Lymphoma ||
* translocation of FGFR1 <ref><pubmed><9425908></pubmed></ref>
||
|-
|Lung Adenocarcenoma ||
*over expression of FGF7 <ref><pubmed><15307144></pubmed></ref> and FGF9 <ref><pubmed><23867472></pubmed></ref> <ref><pubmed><25413587></pubmed></ref>
*FGFR1 amplification <ref><pubmed><21666749></pubmed></ref>
||
*FGFR1 amplification identified in 3% <ref><pubmed><21666749></pubmed></ref>
|-
|Lung Squamous Cell ||
*amplification of FGFR1 <ref><pubmed><24302556></pubmed></ref>
*translocation of FGFR3 <ref><pubmed><23661334></pubmed></ref>
||
*FGFR1 amplification identified in 21-28% cases <ref><pubmed><21160078></pubmed></ref> <ref><pubmed><24302556></pubmed></ref>
|-
|Lung Small Cell||
* over expression of FGF2 <ref><pubmed><11165400></pubmed></ref>
* amplification of FGFR1 <ref><pubmed><24294370></pubmed></ref>
||
*43.7% exhibit FGFR1 amplification, with worse prognostic outcomes <ref><pubmed><24294370></pubmed></ref>
|-
| Lung Non-Small Cell||
*over expression FGF9 <ref><pubmed><24239165></pubmed></ref>
||
*10%, with 3-fold increase in likelihood of post-operative occurrence <ref><pubmed><24239165></pubmed></ref>
|-
| Melanoma <ref><pubmed><8311116></pubmed></ref> ||
*over expression of FGF2
*missense mutation and amplification of FGFR1
||
|-
|Ovarian||
*amplification of FGF1 <ref><pubmed><17538174></pubmed></ref>, overexpression FGF16 <ref><pubmed><24253043></pubmed></ref>
*amplification of FGFR1, over expression of FGFR4 <ref><pubmed><16822847></pubmed></ref> <ref><pubmed><23344261></pubmed></ref>
||
|-
|Pancreatic ||
* amplification of FGFR1 <ref><pubmed><12105858></pubmed></ref>
||
* 2.6-4% <ref><pubmed><23808822></pubmed></ref>
|-
|Prostate||
*over expression of FGF2 <ref><pubmed><23243019></pubmed></ref>, FGF6 <ref><pubmed><10945637></pubmed></ref>, FGF8 <ref><pubmed><12778074></pubmed></ref>, FGF10 <ref><pubmed><18068633></pubmed></ref>, FGF15/19 <ref><pubmed><23440425></pubmed></ref>, FGF17 <ref><pubmed><15129425></pubmed></ref>, polymorphism in FGF23 <ref><pubmed><24053368></pubmed></ref>
*amplification of FGFR1 and FGFR2 <ref><pubmed><14614009></pubmed></ref>
||
*FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers <ref><pubmed><14614009></pubmed></ref>
|-
|}

==New and emerging research surrounding FGFRs==
===Promising therapeutic methods to alleviate the skeletal phenotypes resulting from dysfunction FGFs/FGFRs===
A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors <ref><pubmed>15310757</pubmed></ref>.\
 
 
In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model <ref><pubmed>17694057</pubmed></ref>. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice<ref><pubmed>22072392</pubmed></ref>. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity<ref><pubmed>24048522</pubmed></ref>. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.
 
 
Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression<ref name= "PMID9069288"><pubmed> 9069288</pubmed></ref>. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. <ref name= "PMID9069288"/>.
[[File:Bone signalling pathway1.gif|thumb|400px|Signals regulating bone growth]]
 
 
 
===Emerging Research Into The Role Of FGF In The Development Of The Growth Plate===
https://www.ncbi.nlm.nih.gov/pubmed/25114206
 
===Autoregulatory loop of induction between FGF10 and FGF8 ===
 
 
== Further Information Regarding FGFR Signalling and Embryology==

{| class="wikitable mw-collapsible mw-collapsed"
! Recent Papers From PubMed
|-
|{{Most_Recent_Refs}}
Search term: ''FGF Signalling In Organogenesis''

<pubmed limit=5>FGF Signalling In Organogenesis</pubmed>
|}
{| class="wikitable mw-collapsible mw-collapsed"

 
 
 
==Quiz: How much do you really know about FGF? Take the quiz and find out!==

<quiz display=simple>

{Which of the following statements regarding FGFR3 is true?
|type="()"}
- Mutation in the receptor causes Pfeiffer Syndrome
+ Induces complete growth arrest of cells
- Prevents chondrocytes from developing
- Associated with Kallmann syndrome
||Option B is correct

{Which of the following describes FGFR as a receptor type
|type="()"}
- G-protein coupled receptor
+ Tyrosine kinase receptor
- Electronically coupled receptor
- None of the above
|| Option B is correct

{Which of the following is true
|type="()"}
- FGFR attaches at the outer surface of the lipid bilayer
- FGFR attaches on inner surface of lipid bilayer
+ FGFR cross the membrane and is thus transmembrane
- Options A and B
|| Option C is correct

{How many FGFRs have been discussed in this page?
|type="()"}
- 1
- 2
- 3
+ 4
|| Option D is correct. There are four subtypes of FGFR, with each having various roles in the process of embryonic development.

</quiz>
 

==Glossary==

{| class="pretty table"
|'''Autosomal Dominant Inheritance'''
| A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see [[Abnormal_Development_-_Genetic#Genetic_Inheritance |Genetic Inheritance]]
|-
|'''Craniosysnostosis Syndromes'''
| Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
|-
|'''Ectoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see [[Ectoderm | Ectoderm]]
|-
|'''Endoderm'''
|One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see [[Endoderm | Endoderm]]
|-
|'''Embryonic Axis'''
|
|-
|'''Endochondral Ossification'''
| Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Fibroblast Growth Factors (FGFs)'''
| Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
|-
|'''Fibroblast Growth Factor Receptors (FGFRs)'''
| Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
|-
|'''Gastrulation'''
| Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see [[Gastrulation| Gastrulation]]
|-
|'''Germ Layers'''
| Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
|-
|'''Intramembranous Ossification'''
| It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see [[Lecture - Musculoskeletal Development| Bone Development]]
|-
|'''Limb Bud'''
| The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see [[Musculoskeletal System - Limb Development|Limb Development]]
|-
|'''Lung Bud'''
| The initial embryonic structures responsible for the formation of the lungs. For more information see [[Lecture - Respiratory Development | Respiratory Development]]
|-
|'''Mesoderm'''
| One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.)For more information see [[Mesoderm | Mesoderm]]
|-
|'''Metanephric Kidney'''
|
|-
|'''Missense Mutations'''
| A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
|-
|'''RAS'''
| A family of related proteins which is expressed in all animal cell lineages and organs.
|-
|'''Skeletal Dysplasia'''
| A general term that relates to disorders affecting normal bone development
|-
|}

''Below are links to a more extensive glossary if additional definitions are needed''

[[A]] | [[B]] | [[C]] | [[D]] | [[E]] | [[F]] | [[G]] | [[H]] | [[I]] | [[J]] | [[K]] | [[L]] | [[M]] | [[N]] | [[O]] | [[P]] | [[Q]] | [[R]] | [[S]] | [[T]] | [[U]] | [[V]] | [[W]] | [[X]] | [[Y]] | [[Z]]

''Some external links were included throughout this page.''
{{External Links}}

==References==

<references/>

2016 Group Project 3

2016-10-25T09:50:38Z

Z5015686: /* Quiz: How much do you really know about FGF? Take the quiz and find out! */

User:Z5015686

2016-10-21T02:10:59Z

Z5015686: /* Lab Attendance */

{{ANAT2341Student2016}}

== Lab Attendance==

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:34, 5 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:40, 12 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 19 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 26 August 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 2 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:07, 9 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:33, 16 September 2016 (AEST)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:23, 7 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 14:37, 14 October 2016 (AEDT)

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:10, 21 October 2016 (AEDT)

==Lab 1 Assessment==

<pubmed> PMC4770082 </pubmed>

Short Summary Of Findings

The results of this paper suggest that human oocyte developmental potential can be predicted by the quality and maturation of the oocyte prior to fertilisation, (at the 2PN, pronucleus phase). The experiential design outlined in the paper involved measuring the mechanical properties of mouse and human zygotes using minimally invasive technologies (such as micropipette aspiration) to determine which were most predictive of viability (viability was defined as embryos that would most likely survive to blastocyst stage of development.) The results showed that individual parameters had limited predictive power on viability, however when considered together there was a greater distinction between viable and non-viable embryos. Through the use of statistical analysis it was found that their method of classification to predict embryo blastocyst formation that was based on these mechanical properties had >90% precision, 95% specificity and 75% sensitivity. Mice received embryos that were predicted to be either viable or non-viable based on their mechanical properties, which positively correlated to the mice who later had live births. The experimenters then investigated firstly whether there was a correlation between the viable and non-viable embryos and their gene expression, and secondly how/why these mechanical parameters correlated with viability. Interestingly they found that non-viable embryos had a reduced/different expression of some genes that are important for processes including, but not limited to, regulating cell cycle, oocyte maturation, chromosome segregation, DNA repair and telomere maintenance, thus suggesting that zygote gene expression correlates with viability. They also found that non-viable oocytes might undergo suboptimal fertilisation. Some genes that were identified to be differentially expressed in viable and non-viable embryos are important for fertilisation, including some whose products are found on the oocyte plasma membrane and in its zona pellucida, where if expressed incorrectly could potentially inhibit sperm-egg binding. Additionally, a reduced expression for a gene coding for a sperm protein was identified in non-viable zygotes, as well as a receptor that is involved in initiating the calcium oscillations that leads to cortical granule release and zona-hardening (which assists in the prevention of polyspermy.) Therefore in conclusion, this research demonstrates a way to accurately predict embryo viability early on in development, at the pronucleus stage, suggesting that embryo developmental potential is determined pre-fertilisation. This research has relevant applications in embryo selection process in IVF clinics.

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of the article's main findings. I guess the question is what provides the zygote viscoelastic properties and sperm gene expression?

| width=100px| Assessment 5/5
|}

==Lab 2 Assessment==

[[File:Rbm24a and rbm24b are expressed throughout somitogenesis.jpeg]]

Rbm24a and rbm24b are expressed throughout somitogenesis<ref><pubmed>25170925</pubmed>
[http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105460 PLOSONE]</ref>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - All information Reference, Copyright and Student Image template correctly included with the file and referenced on your page here.
| Assessment 5/5
|}

==Lab 3 Assessment==

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development.

[[Lecture_-_Ectoderm_Development#Primary_Vesicles|Question 3 - brain vesicles]]
| Assessment 4/5
|}

==Lab 4 Assessment==

===Gastrointestinal Quiz===

<quiz display=simple>

{True/False - Gastrulation, gut formation, is a process that occurs during early embryonic development (week 4), whereby the epiblast layer which derives three germ cell layers (ectoderm, mesoderm and endoderm) is divided into three distinct proportions (the foregut, midgut and hindgut) and through a series of rotations and conformational changes contributes to the formation of different GIT structures (including but not limited to, the liver, stomach, intestines, pancreas and spleen)
| type="()"}
+   True
-   False

{Which of the following germ layer components contribute to gastrointestinal development:
|type="[]"}
+ Endoderm
- Somatic Mesoderm
+ Splanchnic Mesoderm
+ Ectoderm (Neural Crest)
|| (1) The Endoderm contributes to the epithelium and associated glands; (3) the Splanchnic Mesoderm contributes to the mesentery, CT, smooth muscle and blood vessels; and (4) the Neural Crest component of the Ectoderm contributes to the development of the enteric nervous system.

{Which of the following statements is '''incorrect''':
|type="()"}
-   The intraembryonic coelom (lateral plate of the mesoderm) is responsible for the formation of the three major body cavities including the pericardial, pleural and peritoneal (where most of the GIT will eventually lie within)
-   Each gastrointestinal tract division can be defined by the vascular artery supply to each, the Foregut by the celiac artery, the Midgut by the superior mesenteric artery and the Hindgut by the inferior mesenteric artery
+   The buccopharyngeal and cloacal membrane degenerate at the same point in time during gastrointestinal development in a normal healthy embryo
-   During embryonic development most of the gastrointestinal tract undergoes some degree of mechanical rotation
|| The cloacal membrane degenerates later after it fuses with the urogenital septum and forms two distinct regions, an anterior binary and dorsal rectal component.

{Which of the following statements regarding gastrointestinal abnormalities is '''most correct''':
|type="()"}
-   The lumen abnormality of duplication, which is the incomplete recanalisation resulting in parallel lumens, is only found to occur in sites located within/surrounding the stomach region
-   Intestinal malrotation displays no clinical symptoms until later childhood
-   Intestinal Aganglionosis is a condition resulting from reduced migration of neural crest cells, (which are responsible for the development of the enteric nervous system and specifically gastric motility) is most commonly experienced higher up in the gastrointestinal tract (towards the oral cavity)
+   Meckel's Diverticulum is the most common GIT abnormality, with an incidence rate of roughly 1-2% in a population
|| (1) Cases of duplication have been found throughout the GIT, including but not limited to the stomach; (2) Clinical symptoms of Intestinal malrotation are present from birth (i.e. neonatals: bilious vomiting and bloody stools); (3) Intestinal Aganglionosis is typically at the anal end of the GIT, and its severity increases the higher up the GIT.

</quiz>

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions, with some minor suggestions for improvement. Question 1 needs an explanation. Question should explain multiple answers are correct. Question 3 has a number of different topics mixed together, not good in MCQs. Question 4 is complicated for most correct type.
| Assessment 5/5
|}

==Lab 5 Assessment==

Completed Course Feedback Questionnaire

[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 13:15, 9 September 2016 (AEST)

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.
| Assessment 5/5
|}

==Lab 6 Assessment==

'''Identify a known genetic mutation that is associated with cleft lip or palate:'''
Mutations in the Interferon Regulatory Factor 6 (IRF6) protein-coding gene (located on chromosome 1) account for the majority of cases of Van der Woude syndrome (VDWS), an autosomal dominant genetic disorder, which has been found to be associated with both cleft lip and cleft palate.

'''Identify a recent research article on this gene:''' PMID 23029012

'''How does this mutation affect developmental signaling in normal development:'''
For the most part the underlying mechanism behind the mutation of the IRF6 gene and the development of cleft lip and palate is largely unknown. However, animal studies involving Irf6 mutant mice have offered an explanation to why this gene could contribute to the development of these abnormalities. These mice presented with hyper-proliferative epidermis failing to undergo terminal differentiation, leading to epithelial adhesions that are able to occlude the oral cavity. IRF6 is also thought to be involved in keratinocyte proliferation and differentiation as well as the formation of the oral periderm. <ref><pubmed>21331089</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/21331089]</ref> Recent research suggests that IRF6 gene interacts with other genes, specifically the Transforming Growth Factor Alpha (TGFA) gene (involved in activating a signalling pathway responsible for cell proliferation, differentiation and development) and may account for up to 10% of cleft lip and cleft palate cases. Interestingly, IRFA knockout mice didn’t express Tgfa in tissues in the palate.
<ref><pubmed>23029012</pubmed> [http://www.ncbi.nlm.nih.gov/pubmed/23029012]</ref>
In summary it is thought that mutations in the IRF6 gene are thought to affect developmental signalling directly or through associations with other genes, however more research is required.

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - [http://www.omim.org/entry/607199 OMIM IRF6] is a good example. It would have been good to describe the full signaling pathway in the last part of the answer.
| Assessment 5/5
|}

==Lab 7 Assessment==

'''What is/are the dystrophin mutation(s)?'''
The dystrophin gene is the largest known human gene and is located on locus Xp21. Mutations of this gene (such as selections, point mutations and duplications) affect the structure/function of the protein dystrophin, and is responsible for causing both Duchenne (DMD) and Becker (BMD) muscular dystrophies<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>, which have a prevalence 4.78 and 1.53 per 100,000 males respectively.<ref><pubmed>24780148</pubmed>[https://www.ncbi.nlm.nih.gov/pubmed/24780148]</ref>
Although they have similar signs and symptoms, they vary in their severity, onset age and rate at which the disease develops - with DND being in general, the more common and severe of the two, appearing earlier in childhood in the from of muscle weakness and rapidly develops, affected individuals have impaired development of normal motor functions. Both are associated with the heart condition cardiomyopathy (weakened cardiac muscles).<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What is the function of dystrophin?'''
Dystrophin is an important cytoskeletal protein, and is a crucial component of the larger dystrophin-glycoprotein complex (DGC) which functions to both stabilise and signal interactions between the cytoskeleton, membrane and extracellular matrix, essentially have a central role in mediating muscle stability. Dystrophin has four main functional domains (actin binding amino terminal, central rod, cysteine-rich domains and carboxyl terminus) which help mediate the complexes interactions with cellular components, for example mediates interactions with actin filaments through the actin binding domain, and interactions with microtubules through the rod domain.<ref><pubmed> 4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What other tissues/organs are affected by this disorder?'''
This disorder is known to result in both cardiac failure and respiratory failure due to the weakening of muscles (as healthy muscle fibres are lost and replaced by fibrosis and fat, and thus have reduced function.)<ref><pubmed>4767260</pubmed> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767260/]</ref>

'''What therapies exist for DMD?'''
Diagnosis of DMD can be confirmed through DNA tests, muscle biopsy (testing for presence or relative size of dystrophin) and even prenatal tests, and although there is no current cure for this disease, some treatments are available to help control age of onset in the hope to maximise affected individuals quality of life. Pharmacological treatments include corticosteriods (including prednisolone and deflazacort) which have shown some benefits in patients such as an improvement in strength, pulmonary function, timed motor function and delaying age at loss of ambulation and cardiomyopathy onset - however, these medications are not without their own set of side effects.<ref><pubmed>26833937</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/26833937]</ref> Current research is looking into the possibility gene therapies which aim to restore dystrophin expression such as the use of viral vectors (acting as vehicles for DMD gene)<ref><pubmed>27215286</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/27215286]</ref>, and antisense oligonucleotide mediated exon skipping. <ref><pubmed>23829870</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/23829870]</ref>

'''What animal models are available for muscular dystrophy?'''
Historically the most popular animal model for muscular dystrophy over the years has been the MDX mouse, the results of which have been shown to be promising and now a larger animal model of canine DMD (cDMD) is being used.<ref><pubmed> 25740330</pubmed> [https://www.ncbi.nlm.nih.gov/pubmed/25740330]</ref>

http://omim.org/entry/300376

http://omim.org/entry/310200

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - Very good.
| Assessment 5/5
|}

==Lab 8 Assessment==
Absent from lab class due to illness

{| width=95%
|-bgcolor="FAF5FF"
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This was an in class quiz on urogenital development. Please see me and you can attempt this assessment.
|}

==Lab 9 Assessment==
‘’Critical assessment of group projects’’ [[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 01:04, 7 October 2016 (AEDT)

===Group 1 – Wnt Signalling Pathway===
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be.

Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development.

In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful.

===Group 2 – Notch Signaling Pathway ===
First impressions of Group 2’s page on the notch-signaling pathway are all positive. Subheadings are very well defined. They have chosen to include a brief yet informative introduction on the pathway, a simple table outlining the major scientific developments over the last 100 years, the molecular mechanisms of the pathway, its specific role in embryonic development (which they have further defined as cardiovascular and CNS), role in animal development, abnormalities relating to this pathway and a glossary. I think another positive aspect of this project, is that they have identified additional subheadings for which they are still to do research on; a particularly important one is current areas of research which not many groups have included. Furthermore, additional positive aspects of this project include the addition of images on the canonical notch signaling pathway and its role in cardiovascular development (which both appear also to be appropriately added to the website), which support the text nicely. It might also be useful to find a relevant video to include just to break up some of the text, and help make the page more interactive. It appears this group has widely researched their topic using both primary and review articles, which are all appropriately referenced using in-text citations. All of these aspects help to clearly convey the necessary information to the reader, and fulfill much of the required criteria of this project. In terms of their written information, Group 2 has included really detailed information on its role in embryonic cardiovascular development, as well as identifying some of the major research articles that have lead to these discoveries and a little bit about them (which then the reader if they are interested it can go read thanks to the inclusion of the in-text citations.) They do include a section of the roles of this pathway in animal development, which is really interesting and goes beyond the normal scope of this course.

Some negative aspects of the project include that, as part of the criteria being that the project has an “element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations” perhaps it would be useful to consider including a hand drawn image when researching the non-canonical pathway or transcriptional regulation of notch signaling, or even of some of the receptor/ligands involved in this signaling pathway. Furthermore, on a similar note it may be important to summarise the receptor subtypes involved in the different pathways, their role in embryonic development and abnormalities of the receptor subtype specifically relating to embryonic development in a table or dot point format. Additionally perhaps more information on its role in the CNS (or other systems during embryonic development) even if its not as detailed as cardiovascular, may help to inform the reader of all of its various roles.

In conclusion, it appears that this project is one of the strongest, it has very clear and informative subheadings separating well researched written material, supported by images sourced from the Internet. The main criticisms were just including your own innovative diagrams or explanations, videos to help make it more interactive and table or dot points summarizing the different receptor subtypes involved in each pathway. Following the completion of this, and the subheadings yet to be researched (and glossary) it appears that this project is going to be very successful in informing peers about the said pathway.

===Group 4 – Hedgehog Pathway ===
Positive aspects of this project include that Group 4 appear to have well defined subheadings, which function well to help the reader navigate through the page. The information is appropriately referenced using in-text citations, appearing to be from both primary and review articles. There is a significant amount of research on the mechanisms of the pathway but less of a focus on the role of this pathway in embryonic development, which I think is really important in order to relate it back to what we are leaning in both the lectures and tutorials. I think the inclusion of current research is a very important aspect to include in this project, as it identifies the current direction in which this research is heading. This might be also interesting to link to its clinical significance and abnormalities in the signaling pathway.

However, some negative aspects of the page include the lack of an introduction as this essentially establishes your page. You need to include a brief outline of the signaling pathway, a summary of its role in development and the other aspects of it you are looking to discuss. Furthermore, the inclusion of an image outlining the signaling pathway without any information inducing or explaining it should be corrected. The project appears to be very informative but isn’t very interactive and lacks images. Perhaps sourcing images of results from some of the primary articles, which you have referenced or include videos outlining the signaling pathway, might be a useful addition. It might be a good idea to include a glossary at the bottom of the page to help readers to better understand some of these more difficult terms. Also under the subheading of history, like in some of the other projects, a table could be a useful addition, just summarizing all the scientific advances regarding this pathway since it was first discovered, this helps set up how far we have come and then may be helpful when talking about the direction in which we are heading under current research.

In conclusion, this looks like it’s on its way to being a successful project. In summary though, a greater emphasis on its role in embryonic development and conscious effort to make the page more interactive and engaging for the reader will go a long way.

===Group 5 – T-Box===
First impressions alone it is extremely clear that Group 5 has thoroughly researched this topic have tried hard to include many diagrams and tables to help separate their information up in order to more successfully convey the information across to the reader. Positive aspects of this project include the well-defined subheadings, making the navigation through the page very easy. The introduction is informative and introduces the following subheadings of the project well. The inclusion of what does T-Box mean is also interesting, setting you apart from the other projects. One of the best aspects of the project would have to be the summary table of the main T-box genes, which includes its main expression sites, its function and abnormalities relevant to the specific gene. You have made a note to include a timeline for the history of the T-Box gene, which I think would be successful in summarizing the scientific advances since its discovery, and also help to break up paragraphs of writing. The project appears to be referenced correctly using in-text citations, only query is whether the links to the PMID articles say in the bottom of cardiac and limb development are references or just articles in which you haven’t written on yet and will be referenced appropriately when you do later. The inclusion of a glossary is also a good idea just to help define and explain some of the more difficult terms mentioned.

As for negative aspects of the project, there wasn’t too many. Like for every project, in terms of making it more interactive it might be a good idea to include a YouTube video or animation of the signaling pathway or its role in a specific developmental process, as well as your own hand-drawn image just to fulfill the necessary criteria of this assignment. Furthermore, with some of the smaller images that don’t go the full width of the page, it might be a nice idea to align them to the right as a thumbnail next to their relevant text, so readers see them whilst reading about it. Also remember to make a reference the image you have chosen in your text to emphasise its importance to what you are actually talking about. Although the subheading “good places to look” might just be something for you guys while researching, I think that you could utilize this by including various links with more information on the relevant topics of which you have discussed. This would help to make you page more interactive as well.

This project appears to be extremely well done and is definitely one of the strongest. Most of the criticisms are regarding the formatting of the page and making it more interactive for the reader. All in all this is very well researched project!

===Group 6 – TGF-beta===
You guys have made a good start to the project identifying some important subheadings introducing the TGF-beta signaling pathway, outlining its history, current research and limitations (which may be more appropriately labeled as abnormalities.) However, I do think the structure of these should be revised, what I mean by this is that you should create more levels of headings (as currently all the headings are located under the larger heading of introduction.) Furthermore, it terms of the headings, I think you need to introduce the signaling pathway, then discuss the history of its discovery, then discuss the specific mechanisms behind the pathway, its role in embryonic development (which is a very important aspect in order to relate your project back to what we are learning in the lectures and tutorials), then animal models and abnormalities. You have chosen to include some images which appear to be useful for explaining the signaling pathway, however I think it is important to refer to them in your text, as well as appropriately referencing them with the copyright from the original source (as the larger one is missing this information.)

Some negative aspects of this project are the lack of appropriate references, there are no in-text citations and the identified sources that have been used appear to be websites. Remember that most of the information, if not all should be acquired from primary research articles (supplemented with the occasional review article.) Furthermore, similar to other projects, in order to make your page more engaging you could look into including tables (say for the history or summary of receptor subtypes), more images, YouTube links or animations, or an interactive quiz.

In conclusion it seems that there is still a lot of work to be completed on this page before it is to be submitted, however you have made a successful start. The main criticisms are regarding revisiting the subheadings and including the role of embryonic development as I think this is really critical to the project, as well as adding more information to the page in general. In saying that it appears you guys are heading in the right direction!

{{Stem Cell Presentations 2016}}

==References==
<references/>

[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]
PMID 27486480

2016 Group Project 3

2016-10-19T11:42:24Z

Z5015686: /* Signal Transduction */