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[[File: FGF signalling pathway.jpg|700px|thumb|centre|FGFR Signalling Pathway<ref><pubmed>27458533</pubmed></ref>]]
[[File: FGF signalling pathway.jpg|700px|thumb|centre|FGFR Signalling Pathway (Image based upon<ref><pubmed>27458533</pubmed></ref>)]]


''- Different transduction pathways it has''
''- Different transduction pathways it has''

Revision as of 17:51, 28 September 2016

2016 Student Projects 
Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta
2016 Group Project Topic - Signaling in Development

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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 organ, vascular and skeletal development. Furthermore, this pathway is also 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.) [1]

History

Fibroblast growth factor (FGF) was initially discovered in pituitary extracts through experiments conducted in 1973. 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.

(add timeline)

Overview Of The FGFR Pathway

22 protein families of 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) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). [2]

FGFRs are comprised of 3 immunoglobulin domains (IgI-III), with IgIII being the closest to the transmembrane, and IgI being the furthest away. As shown in the image, an acidic box (AD) is located in-between IgI and IgII, IgII contains a heparin-binding domain (HBD), which is important in signal transduction, and IgIII is a transmembrane structure with kinase and interkinase domains (KD and IKD) within the intracellular space. [3]

Signal Transduction


The process of signal transduction commence 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[4]. 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) [5].

In turn, these sequence of events promote 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 [6].

With respect to embryonic development, both the PI3K and RAS pathways are essential in order for normal mesoderm to occur 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 [7].



FGFR Signalling Pathway (Image based upon[8])

- Different transduction pathways it has

- Add image

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 us spread along the neural tube by cell movements of convergence and extension. In the process by which cells are driven out of the tube, they change their pattern of movement which eventually causes a gradual restriction in space[9]. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells prematurely to leave the stem cell region and to change their movement patters as if they had aged[10].

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.

Induction/Maintenance Of Mesoderm And Neuroectoderm

Organogenesis

Limb Bud

Limb buds are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are structures formed early in limb development, roughly 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.[11] 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 WNT3 (and downstream transcription factors including SP6 and SP8)[12] 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,[13] and subsequently stimulate FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping in mitotically active state, and stimulating a positive feedbacks loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout, although other FGFs are expressed in the posterior of the AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.[14][15] FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain Fgf10 expression.[16]

- Zone of polarizing activity (ZPA)

- Interaction with SHH

- FGF signaling is also involved in lung initiation and development, and has similar underlying process.

Kidney/External Genitalia


James


Inner Ear Development

Animal Models

(jocelyn)

Abnormalities (Kristine)

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.

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. [17] 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).[18] 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. [19]

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.


Pfeiffer Syndrome

Mutations in FGFR1 and FGFR2

Apert Syndrome

Mutations in FGFR2: S252W

Glossary

(Manraaj)

References

  1. <pubmed>25772309</pubmed>[1]
  2. <pubmed>25772309</pubmed>[2]
  3. <pubmed>16216232</pubmed>[3]
  4. <pubmed>1655404</pubmed>
  5. <pubmed>11021964</pubmed>
  6. <pubmed>1656221</pubmed>
  7. <pubmed>9632781</pubmed>
  8. <pubmed>27458533</pubmed>
  9. <pubmed>8575335</pubmed>
  10. <pubmed>11389440</pubmed>
  11. <pubmed>9620845</pubmed> [4]
  12. <pubmed>15358670</pubmed> [5]
  13. <pubmed>25772309</pubmed> [6]
  14. <pubmed>11101846</pubmed> [7]
  15. <pubmed>12152071</pubmed> [8]
  16. <pubmed>25109552</pubmed> [9]
  17. <pubmed>7913883</pubmed>[10]
  18. <pubmed>12816345</pubmed>[11]
  19. <pubmed>8723101</pubmed>[12]


Extra Resources

Useful review articles that may be worth a read through:


http://onlinelibrary.wiley.com/doi/10.1002/wdev.176/full

http://www.nature.com.wwwproxy0.library.unsw.edu.au/nrd/journal/v8/n3/pdf/nrd2792.pdf

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160605006184

http://www.nature.com.wwwproxy0.library.unsw.edu.au/nrm/journal/v14/n3/full/nrm3528.html

http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/jcp.24649/full

http://genesdev.cshlp.org/content/29/14/1463.full (FGF signalling and skeletogenesis, specifically how mutations to the FGF signalling pathway may be responsible for skeletal diseases)