New roles of Notch in a neural cell

Abstract

The transmembrane receptor Notch and its ligand Delta are components of the highly conserved Notch signaling pathway that is required to regulate multiple developmental decisions. The most studied role of Notch is lateral inhibition, in which neural precursors inhibit neighboring cells in the proneural region from adopting a neural cell fate. During lateral inhibition, Delta binding leads to Notch activation releasing the Notch intracellular domain, which regulates the target gene expression. During neural specification, both Notch and Delta are ubiquitously expressed in the proneural region of Drosophila, raising the question of how neuron cells are specified from a specific subset of cells during normal development.;Using the specification of the R8 photoreceptor in the Drosophila eye as a model system, I demonstrated the mechanism of Notch proneural enhancement, which is required during specification of R8 precursor cell prior to lateral inhibition.;Notch proneural enhancement occurs in all the cells, where lateral inhibition must be prevented in the R8 precursor cells. By the study of a Notch mutant allele called split, I proposed that activating Notch signaling in non-R8 cells is only one part of story and inactivating Notch signaling is the other part of story. I found that the split mutation is unable to protect R8 precursor cells from lateral inhibition, due to the modification of EGF repeat 14 of Notch.;Two other genes scabrous and gp150 are essential for split to affect neural development and together might define a genetic pathway affecting Notch activity in R8 precursor cells. I showed that scabrous and gp150 were localized in endosomes, and they promoted Notch signaling through the same pathway, with Gp150 acting downstream in cells that respond to secreted Scabrous protein.;Another gene neuralized, encoding an ubiquitin ligase, promotes Notch signaling by ubiquitinating Delta. This raises the possibility that Neuralized might function through the same mechanism as Scabrous and Gp150. I showed that Neuralized was not required in the same cells as Scabrous and Gp150, indicating that Neuralized function is distinct from Scabrous and Gp150.