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Shh signaling pathway overview
- Hedgehog binds to Patched protein. This binging RELEASES inhibition to Smoothened, allowing it to INHIBIT both PKA and Slimb. With these blocked, Ci protein can be made into an activator, where it translocates to the nucleus and aids in transcription.
- Without Hedgehog, Patched acts to INHIBIT Smoothened, therefore allowing both PKA and Slimb to cause Ci to act as a repressor, splitting Ci into two components, one which is phosphorylated and the other acting as the REPRESSOR to stop transcription.
DEVELOPMENTAL EVENT THAT UTLIZES SHH PATWHAY
- Hedgehog plays a role in limb bud development.
- 1.) patterning within limb bud thru promoting expression of downstream genes such as Hoxd and Bmp-2
- 2.) role in establishing anterior-posterior limb axes
- Shh creates POSITIVE feedback loop with AER to produce Fgfs, which is needed to maintain ZPA as well as Shh expression.
1st EXPERIMENTAL APPROACHES FROM THE PAPER THAT SUPPORTS A ROLE FOR SHH signaling IN THIS DEVELOPMENTAL EVENT:
- In the Laufer et al paper, in situ hybridization experiments showed Shh promotes expression of downstream genes involved in patterning in limb bud.
- Using embryos ectopically injected with Shh virus, expression of Hoxd genes was visualized via radioactive probes at multiple time points.
- Results show: Shh expression occurred first, followed by Hoxd-11 and -13 at the later time points. The authors concluded that Shh has the ability to PROMOTE DOWNSTREAM Hoxd genes
2nd EXPERIMENTAL APPROACHES FROM THE PAPER THAT SUPPORTS A ROLE FOR SHH signaling IN THIS DEVELOPMENTAL EVENT:
- In situ hybridization experiments also show Shh can induce FGFs in the AER.
- Shh virus injected anteriorly into the embryos, versus posteriorly (where Fgf-4 is normally found) and probes used to visualize FGF-4 expression.
- Results show: FGF-4 was detected near the Shh injection sites, at sites AWAY from the posterior end of the embryo.
- This data suggest that Shh can induce FGFs and that Shh interacts with the AER. Showing a link between Shh and Fgf-4 is needed to show that feedback loop is created between these molecules.