Genes in development Signal transduction pathways and transcription factors.

A restriction in developmental potential can be viewed as the acquisition of a unique transcriptional state In other words, a specific combination of genes are expressed in a particular cell type. As we have now seen, there are only two ways that the developmental potential of an embryonic cell can be restricted.

(i) the inheritance of a unique mRNA or protein

(ii) the reception of a signal from another cell Cell interactions can take different forms and involve distinct signalling components

Paracrine signaling A molecule (usually a small protein) made by one cell is secreted and diffuses to receptors on a neighbouring cell. Binding of the secreted molecule causes a cascade of protein interactions in the receiving cell, usually leading either to activation or repression of transcription. Paracrine signaling can also lead to a change in cell shape, by causing changes to the cell cytoskeleton. These types of cell-cell interactions are usually only effective over a few cell diameters.

fgf8 is expressed in presumptive limb buds Examples Paracrine Signaling Factors are categorized according to the structure of the receptors fgf8 is expressed in presumptive limb buds

1. Ligand binding results in dimerization and auto-phosphorylation 2. Autophosphorylation activates bound proteins, each of which is used to activate or inactive RAS protein, via GDP/GTP cycling 3. When RAS is active, it activates several other kinases, the last of which enters into the nucleus where it phorphorylates and activates transcription factors. Control of RAS activity is a critical part of the regulation of this pathway. In humans, mutations that prevent inhibition of binding of RAS to GAP are associated with cancer

The hedgehog family of signal transduction pathways Hedgehog requires cholesterol for cleavage of hedgehog from apo- to holoprotein and diffusion through the extracellular matrix 1. When hedgehog is not bound Patched inhibits Smoothened If smoothened is inhibited, PKA and Slimb phosphorylate Ci, which causes cleavage. Part of the cleaved Ci protein is a transcriptional repressor. 2. When ligand binds, PKA and Slimb are inhibited. This stabilizes Ci, which then binds a transcriptional co-activator called CBP and results in transcription Derepression is, again a major consequence of signal reception.

Read up on TGF-beta signaling. 8e; page 155 9e; page 95

Juxtacrine Signaling Two cells are in direct physical contact via interactions with receptors at the cell surface.

Example of Juxtacrine Signaling: The Delta/Notch pathway. Transmembrane proteins are present on both sending and receiving cells. Contact between these proteins causes proteolytic cleavage of the intracellular part of the receptor. The cleaved protein enters the nucleus where it de-represses transcription by interacting with proteins.