Genetic and Molecular Analysis of Strawberry Notch

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

Notch (N) signaling is important for many different intercellular communications events that are critical for proper development. This pathway has been conserved from worms to humans and has functional consequences for many different tissues types. Mutations in the members of the Notch pathway in humans have been implicated in the development of cancer, Alagille syndrome, CADASIL and in Alzheimer's disease. Two different kinds of Notch signaling have been described in the literature. The first, called lateral signaling, is a mechanism by which cells that are initially equivalent, interact through this pathway and create a pattern in which only a fraction of the cells are biased to assume a differentiated fate. This involves an interactive process that requires repeated Notch signaling via feedback loops. In contrast, during inductive Notch signaling, the signaling cell is intrinsically distinct from the one receiving the signal. The signaling causes the activation of fate-specifying molecules in the cell receiving the signal. Most identified members of the Notch signaling are widely expressed and participate in both inductive and lateral inhibition pathways. What then causes the distinction between these different signaling events? Genetic analysis in Drosophila has shown that Strawberry Notch (sno) functions as a positive component of the Notch signal transduction pathway. The sno gene encodes a highly conserved nuclear protein that is expressed in all ectodermally derived tissue. Studies aimed at determining the function of this gene showed that sno participates in many different inductive signaling processes initiated by the Notch receptor, but does not have any function in lateral signaling by Notch. More recently, sno has been shown to be important for the expression of the Notch ligand, Delta in R cells of the Drosophila eye. The RTK signal mediated by the EGF pathway was also shown to contribute positively in this process. Two proteins, Sno and Ebi, are responsible for alleviating this repression. These results suggest that Sno and Ebi function in conjunction with the EGFR pathway to depress Su(H) through proteasome mediated degradation of co-repressors. Thus, the difference between the lateral inhibitory and inductive Notch signaling does not reside in events downstream of Notch. Rather, this distinction is a result of the differences in the way the Notch ligand Delta is controlled. Sno is an important link between RTK and Notch pathways in this process. The current proposal is aimed at studying the biochemistry of Sno function in S2 and cl-8 cells to determine if it indeed directly participates in the derepression of Su(H) targets. Genetic studies suggest that deltex (dx) exhibits strong genetic interaction with sno. This proposal is aimed at studying the possible role of dx in the regulation of Delta in association with Sno. Finally, the sequencing to the Drosophila genome has led to the identification of a gene similar to sno called sno-related (snor). Genetic and molecular characterization of this gene are proposed. Taken together, we expect to unravel the mechanism for proteasome mediated regulation of multiple signaling pathways by Sno-like proteins.