2016 Group Project 3

2016 Student Projects
Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta
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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.)

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).

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.

Signal Transduction

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.

- 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. 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.

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.

Organogenesis

Limb Bud

Limb buds which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm, are formed roughly week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers. FGF signaling (along with its interactions with other signaling pathways) is critical for the initiation and proximal-distal growth of limbs from a limb bud structure. Prior to bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. (REF) FGF10 is responsible for stimulating the expression WNT3 (and downstream transcription factors including SP6 and SP8) 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, and subsequently stimulate FGF8. FGF8 is responsible for continued growth of the underlying mesoderm (keeping in mitotically active state?) and positive feedbacks on FGF10 (stimulating 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. FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain Fgf10 expression.

- 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

Animal Models

(jocelyn)

Abnormalities

(Kristine)

Glossary

(Manraaj)

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)