LET-23-MEDIATED SIGNAL-TRANSDUCTION DURING CAENORHABDITIS-ELEGANS DEVELOPMENT

We are using Caenorhabditis elegans vulval induction to study intercel lular signaling and its regulation. Genes required for vulval inductio n include the LIN-3 transforming alpha-like growth factor, the LET-23 epidermal growth factor (EGF)-receptor-like transmembrane tyrosine kin ase, the SEM-5 adaptor protein, LET-60 Ras, and the LIN-45 Raf serine/ threonine kinase. Inactivation of this pathway results in a failure of vulval differentiation, the ''vulvaless'' phenotype. Activation of th is pathway either by overexpression of LIN-3, a point mutation in the LET-23 extracellular domain, or hyperactivity of LET-60 Ras results in excessive vulval differentiation, the ''multivulva'' phenotype. In ad dition to searching for new genes that act positively in this signalin g pathway, we have also characterized genes that negatively regulate t his inductive signaling pathway. We find that such negative regulators are functionally redundant: mutation of only one of these negative re gulators has no effect on vulval differentiation; however, if particul ar combinations of these genes are inactivated, excessive vulval diffe rentiation occurs. The LIN-15 locus encodes two functionally redundant products, LIN-15A and LIN-15B, that formally act upstream of the LET- 23 receptor to prevent its activity in the absence of inductive signal . The LIN-15A and B proteins are novel and unrelated to each other. Th e unc-101, sli-1, and rok-1 genes encode a distinct set of negative re gulators of vulval differentiation. The unc-101 gene encodes an adapti n, proposed to be involved in intracellular protein trafficking. The s li-1 gene encodes a protein with similarity to c-cbl, a mammalian prot o-oncogene not previously linked with a tyrosine kinase-Ras-mediated s ignaling pathway. LlN-3 and LET-23 are required for several aspects of C. elegans development-larval viability, P12 neuroectoblast specifica tion, hermaphrodite vulval induction and fertility, and three inductio ns during male copulatory spicule development. Fertility and vulval di fferentiation appear to be mediated by distinct parts of the cytoplasm ic tail of LET-23, and by distinct signal transduction pathways. (C) 1 995 Wiley-Liss, Inc.