SynMuv Genes Redundantly Inhibit lin-3/EGF Expression to Prevent Inappropriate Vulval Induction in C. elegans

Abstract

Activation of EGFR-Ras-MAPK signaling in vulval precursor cells (VPCs) by LIN-3/EGF from the gonad induces vulval development in C. elegans. The prevailing view is that LIN-3 overcomes an "inhibitory signal" from the adjacent hyp7 hypodermal syncytium. This view originated from observations indicating that inactivation of functionally redundant Synthetic Multivulva (SynMuv) genes in hyp7 can activate EGFR-Ras-MAPK signaling in the VPCs. Many SynMuv genes encode transcription and chromatin-associated factors, including the Rb ortholog. Here, we show that the SynMuv A and SynMuv B gene classes are functionally redundant for transcriptional repression of the key target gene, lin-3/EGF, in the hypodermis. These observations necessitate a revision of the concept of "inhibitory signaling." They also underscore the importance of preventing inappropriate cell signaling during development and suggest that derepression of growth factors may be the mechanism by which tumor suppressor genes such as Rb can have cell nonautonomous effects.

RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans

“…Adult or L4 worms were used for counting intestinal nuclei in strains containing elt-2::gfp/LacZ reporter. RNAi by feeding was performed as described (7 13-dependent genes that we tested by real-time RT-PCR, sod-3, had an increased expression in unc-13(e1091) background compared with wild type (data not shown). However, its expression was even higher in the lin-35unc-13 strain.…”

“…The C. elegans Rb protein LIN-35 represses inappropriate transcription of germline-specific genes (12) and growth factors (13) in differentiated somatic cells and functions redundantly with other transcriptional repressors (14). Also, lin-35 mutants are more sensitive to exogenous RNAi than wild-type worms (11,15).…”

Multiple Levels of Redundant Processes InhibitCaenorhabditis elegansVulval Cell Fates

“…In this article, 1 we show that these putative class C synMuv genes are not distinct from and should be considered class B synMuv genes. The gene lin-3, which encodes the EGF-like ligand of the RTK/Ras pathway required for the specification of vulval cell fates (Hill and Sternberg 1992), is an apparent direct or indirect transcriptional target of at least some synMuv genes (Cui et al 2006). Given this observation and the molecular nature of many synMuv proteins, the synMuv proteins likely act as transcriptional repressors to prevent the ectopic expression of the RTK/Ras pathway ligand LIN-3 and in this way prevent ectopic vulval induction.…”

“…The penetrances of synMuv vulval phenotypes correlate with the level of lin-3 mRNA expression: Cui et al (2006) reported that the lin-3 gene, which encodes the EGF ligand of the Ras pathway is a transcriptional target of some synMuv proteins. Three double mutants carrying a class A and a class B synMuv mutation had increased lin-3 EGF mRNA levels.…”

Wnt signal from multiple tissues and lin-3 /EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans

“…Constitutively active Wnt signal transduction causes VPCs that normally adopt the 3°fate to be ''overinduced'' (as assessed by ectopic invaginations), even when EGFR-Ras-MAPK activity is reduced (28). However, a situation in which Wnt signaling is artificially activated may be misleading as an indication of its normal role; a cautionary tale is afforded by the effect of removing SynMuv gene activity, which creates an artificial signaling event (32). In addition, lin-39 activity both prevents fusion and promotes division (4); thus, it is conceivable that abnormally high lin-39 levels in pry-1 mutants (perhaps in combination with other ectopically elevated factors) could cause spurious division so that P4.p or P8.p may divide ectopically without having responded to normal patterning signals.…”