Project Summary We will continue our study of genes needed for neuronal differentiation and function using the six touch receptor neurons (TRNs) of the nematode Caenorhabditis elegans. Our previous research identified genes needed for the generation, specification, maintenance and function of the TRNs. In the last few years we 1) identified genes needed for the specification of neuronal subtypes; 2) discovered a new activity of transcription factors, including Hox proteins (as “guarantors”) that maintains transcription factor expression by the restricting its stochastic expression; 3) examined the how the release of epigenetic inhibition affects the terminal differentiation of subtypes of motor neurons; 4) discovered several behaviors that modulate TRN touch sensitivity, including a previous unstudied type – long-term sensitization – and the mechanisms underlying these modulations; 5) identified a role for integrins and other focal adhesion proteins in neuronal mechanosensation; 6) discovered that the -tubulin acetyltransferase MEC-17 specifies the unusual, 15-protofilament structure of TRN microtubules; 7) discovered a new type of chaperone for the mechanosensory transduction channel; 8) determined the stoichiometry (MEC-42MEC-10) of the transduction channel; and 9) investigated the roles of the Wnt signaling pathway, Rac GTPases, and GEFs in process outgrowth. The general goal of the research going forward is to exploit these findings to understand how the differentiation of individual cell types is controlled and how mechanical inputs are sensed and modified. We plan to discover and characterize genes needed for TRN differentiation, specifically those needed for the differences among TRNs and TRN process outgrowth and ensheathment and to investigate touch sensitivity and its control by investigating newly identified lethal genes needed for touch sensitivity by testing and characterizing TRN-expressed genes for supersensitivity, and by studying the role of neuropeptides. The health relatedness of our work comes from the discovery of new genes and new interactions among genes that are similar in humans and other mammals.