IDENTIFICATION AND CHARACTERIZATION OF GENES THAT INTERACT WITH LIN-12 IN CAENORHABDITIS-ELEGANS

We identified and characterized 14 extragenic mutations that suppresse d the dominant egg-laying defect of certain lin-12 gain-of-function mu tations. These suppressors defined seven genes: sup-17, lag-2 sel-4, s el-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recess ive suppressors, whereas the two mutations that define the seventh gen e, lag-2 are semi-dominant suppressors. These suppressor mutations wer e able to suppress other lin-12 gain-of-function mutations. The suppre ssor mutations arose at a very low frequency per gene, 10-50 times bel ow the typical loss-of-function mutation frequency. The suppressor mut ations in sup-17 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause leth ality. Temperature-shift studies for two suppressor genes, sup-17 and lag-2, suggest that both genes act at approximately the same time as l in-12 in specifying a cell fate. Suppressor alleles of six of these ge nes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of t hese suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.