CSB Lecture 9 Summary

By Axel Blom, s1518410/4399307

Several genes are involved in regulating development and differentiation. Notchreceptor based signaling can affect differentiation, proliferation and apoptosis in
neighboring cells. When a ligand binds, the receptor is cleaved and the
intracellular part travels to the nucleus to regulate transcription. The old
paradigm was that Notch signaling is linear and without significant cross-talk with
other pathways. Recently, however, knock-outs and RNAi screening of the
Drosophila genome by looking at several morphologic indicators revealed that
the Notch pathway is connected to many other signaling pathways.
Notch is also involved in somitogenesis together with fibroblast growth factor
(FGF). This is explained by the clock-and-wavefront model: An oscillatory clock
induced by several genes, among which Notch, moves towards the somites while
a gradient of FGF slowly recedes from the somites. Only when FGF is minimal and
the oscillation is present, a segment will be formed, regulating its size and
location. This is induced by Mesp2, which is activated by Notch and indirectly
suppressed by FGF by phosphorylation of ERK.
There are 18 FGFs and 4 different FGF-receptors, but even more splicing isoforms.
It plays a role in endocrine signaling with the Klotho co-receptor and in paracrine
signaling with the heparan sulphate co-factor. FGF binding to a receptor induces
dimerization and autophosphorylation, activating a signaling cascade. The
different FGFs have different effects on motility, proliferation and survival. For
example, because FGF10 binds stronger to heparan sulphate than FGF7, the
morphogenic effect is contained more locally when FGF10 binds. FGF9 is
regulated by inactivation when homodimers form. Reduced homodimerization
and binding to heparan sulphate of FGF9 causes synostosis.
The difference in splicing isoforms FGF8a and FGF8b is very important, because
only FGF8b interacts with FGFR2c, which is crucial for cerebellum formation. The
different splicing isoforms of FGF-receptor produced by mesenchymal and
epithelial cells allows them to react specifically to the same ligand and eachother
by slight conformational variations.