Conservation and change of Notch pathway regulation mechanisms

The Notch pathway controls inter-cellular communication in higher eumetazoa, thereby allowing tissue specific cell differentiation during development. The name giving Notch-receptor binds to membrane-anchored ligands (named Delta and Serrate or Jagged) on neighboring cells. Subsequently Notch is cleaved and the intracellular domain travels into the nucleus, where it acts as a transcriptional co-activator of Notch target-genes. The structure of the activator complex has been solved; its core components are the DNA-binding protein CSL [mammalian RBP or CBF1, Drosophila Su(H) and worm Lag1], and the coactivators Mam and intracellular Notch. A number of additional proteins are known to act as coregulators as well, for example Skip [BX42 in Drosophila]. In the absence of ligand, i.e. intracellular Notch, Notch target genes are silenced. In this case, CSL assembles a repressor complex that includes several components, e.g. mammalian KyoT2 or Sharp (or Mint), which recruit general corepressors like the C-terminal binding protein CtBP. In Drosophila,  Hairless acts as the major Notch antagonists: it binds to Su(H) and recruits corepressors dCtBP and Groucho.

In addition to the transcriptional regulation, Notch signalling underlies many additional regulatory input, including endocytic ligand activation and receptor turn over, as well as nuclear export of RBP by help of Rita.

Most members of the Notch signalling cascade are extremely well conserved between vertebrates and invertebrates. Only few examples stand out, including Rita, which is not present in insects, or Hairless, which appears restricted to insects.

We are investigating the structural and functional conservation of these and other components of the Notch pathway, in order to define their respective roles and their likely homologues.