A strawberry notch homolog, let-765/nsh-1, positively regulates lin-3/egf expression to promote RAS-dependent vulval induction in C. elegans

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.03.004 Byline: Carrie L. Simms, David L. Baillie Keywords: EGF; lin-3; RAS; Vulval induction; Strawberry notch; Notch; Transcription Abstract: The specification and patterning of vulval precursor cells (VPCs) in C aenorhabditis elegans is achieved using a conserved EGFR/RAS signaling pathway that is activated by the ligand lin-3/EGF, which is secreted by the neighboring somatic gonad. Previous work has demonstrated that the expression of lin-3 must be tightly regulated to ensure that only three of six equivalent VPCs are induced to differentiate into the mature vulva. Here, we have identified a novel regulator of EGFR/RAS signaling, let-765/nsh-1, that functions upstream of the pathway to promote vulval induction. let-765 encodes a conserved DExD/H box helicase protein and is the C. elegans ortholog of Drosophila strawberry notch. By investigating genetic interactions between let-765 and RAS pathway genes as well as with synthetic multivulva (synMuv) genes, we have demonstrated that let-765 positively regulates the RAS pathway and antagonizes synMuv activity at the level of lin-3/EGF. In support of these proposals, we found that LET-765 is required for producing wild-type levels of lin-3 mRNA. Mutations in let-765 result in pleiotropic phenotypes that imply its function must be required in multiple developmental processes and, together with data presented here, suggest that LET-765 promotes the expression of diverse targets, potentially through interactions with transcriptional activator or repressor complexes. Author Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, B.C., Canada Article History: Received 3 September 2009; Revised 2 March 2010; Accepted 8 March 2010