2016 Group Project 3: Difference between revisions
No edit summary |
No edit summary |
||
Line 20: | Line 20: | ||
===Signal Transduction=== | ===Signal Transduction=== | ||
<br> | <br> | ||
<p>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<ref><pubmed>1655404</pubmed>. 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>. | <p>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<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>. | ||
<br> | <br> | ||
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 <ref><pubmed>1656221</pubmed>. | 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 <ref><pubmed>1656221</pubmed></ref>. | ||
<br> | <br> | ||
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 <ref><pubmed>9632781</pubmed>. | 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 <ref><pubmed>9632781</pubmed></ref>. | ||
</p> | </p> | ||
Revision as of 13:43, 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
OK you are now in a group, add a topic with your student signature to the group page. | ||||
This page is an undergraduate science embryology student project and may contain inaccuracies in either descriptions or acknowledgements. |
Group Assessment Criteria |
---|
Science Student Projects
|
More Information on Assessment Criteria | Science Student Projects |
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].
- 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[8]. 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[9].
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 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.[10] 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)[11] 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,[12] 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.[13][14] FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain Fgf10 expression.[15]
- 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)
Achondroplasia
Achondroplasia is a common form of dwarfism and its appearance is characterised as shortened proximal limbs, curvature of the spine, a large prominent forehead and fattened nasal bridge. It is a result of a mutation in the FGFR3 gene which decreases the inhibition of endochondral ossification (as arginine is substituted for glycine, G380R.)
Mutations in FGFR3: G380R
Thanatophoric Dysplasia
Mutations in FGFR3: R248C or K650E
Pfeiffer Syndrome
Mutations in FGFR1 and FGFR2
Apert Syndrome
Mutations in FGFR2: S252W
Glossary
(Manraaj)
References
- ↑ <pubmed>25772309</pubmed>[1]
- ↑ <pubmed>25772309</pubmed>[2]
- ↑ <pubmed>16216232</pubmed>[3]
- ↑ <pubmed>1655404</pubmed>
- ↑ <pubmed>11021964</pubmed>
- ↑ <pubmed>1656221</pubmed>
- ↑ <pubmed>9632781</pubmed>
- ↑ <pubmed>8575335</pubmed>
- ↑ <pubmed>11389440</pubmed>
- ↑ <pubmed>9620845</pubmed> [4]
- ↑ <pubmed>15358670</pubmed> [5]
- ↑ <pubmed>25772309</pubmed> [6]
- ↑ <pubmed>11101846</pubmed> [7]
- ↑ <pubmed>12152071</pubmed> [8]
- ↑ <pubmed>25109552</pubmed> [9]
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)