Dale

1) Transmembrane ligand protein (Cell sending cell) interacts with the transmembrane receptor (Notch in the receiving cell).

2) A number of cleavage events takes place. The last is mediated by gamma secretase.

3) During the protease events, the notch intracellular domain is cleaved and that goes into the nucleus, forms a complex with other proteins and activate its target genes.

• either by blocking it: by interfering with that gamma secretase activity

• interfere at the level of transcription: introduce a dominant negative form called RPP.

  That cannot bind DNA and will soak up all the NICD so that it doesn't get to activate target genes.

• we can activate the pathway by introducing just the cleaved bit of the receptor.

• They share the same basic body plan of the embryo.

  Head and tails axis, somites repeated blocks of mesodermal tissue, and the nervous system.

• Chicks develop fast > good to track sign. pathways

Yes.

In this way it directs which cell fate stem cells adopt.

• Morphogen changes the fate of cells, in a concentration dependent manner.

  ⬇️ e.g.

• Sonic hedgehog (Shh) is a factor which is released by the notochord and diffuses across the neural epithelium.

As a result of receiving different concentrations of hedgehog, different genes are turned on. This creates a pattern.

The genes that are turned on are markers that determine what type of neuron neural progenitors cells will become.

1) Harry is regulated by Shh.

2) cHairy2 induces transduction of the Shh signal downstream of ligand (it makes cells act as if they see more Shh).

3) Loss of Notch signalling leads to dramatic reduction of FP domain.

4) Mis-expressing cHairy2/NICD expands the FP domain of the markers.

Notch is required for high dose responses to Shh to pattern the ventral neural tube.

—> expanding Notch > expanding ventral marker

In the abscence of Shh, Notch can move Smo into the cilium.

With Notch, Smo is pushed into the cilium

1) When there is no Shh signal at the receptor of the transmembrane protein Ptc1 sits on the cilium.

2) It’s job is to inhibit another transmembrane protein called Smo. 3) The transcription factor stops gene activation. Gli is cleaved into a repressor

4) Shh binds to Ptc1 & moves out of the cilium. Ptc1 is no longer repressing Smo

5) Smo prevents cleavage of Gli.

6) Gli goes in and activate its target genes.

CDKs (they move cells through the cell cycle) are involved in phosphorelation of Notch

If phosphorelation is stopped > degredation is stopped