The nervous system comprises diverse and highly specialized neuron-types, each expressing a unique set of genes that define its functional properties. What molecular mechanisms generate diverse neuron types remains a central question in neuroscience. Study of C. elegans chemosensory BAG neurons showed that a
p38 MAP kinase (MAPK), PMK-3, is required for their proper differentiation. How
p38 MAPKs function in neurodifferentiation is poorly understood. To identify molecules that function with PMK-3, we performed a reporter-based screen for mutations that restored expression of a BAG fate-marker to
pmk-3 mutants. This screen isolated eighteen mutations, including five loss-of-function alleles of
unc-31.
unc-31 encodes the ortholog of CAPS, which functions to promote Ca2+-dependent exocytosis of dense core vesicles (DCVs). This suggests that neural activity and regulated secretion oppose PMK-3 in regulating neuronal gene expression. Indeed we find that genes that promote neural activity and secretion also mutate to suppress
pmk-3. Silencing only BAG neurons sufficed to restore gene expression to
pmk-3 mutants, and we found that regulated neurosecretion is required during development to antagonize PMK-3-dependent gene expression. To identify the factors secreted in an
unc-31-dependent manner, we tested mutants linked to distinct types of secreted peptide factors for suppression of
pmk-3. Knock-down of the insulin receptor DAF-2 in BAG neurons restored gene expression and function to
pmk-3 mutant neurons. Strikingly, we found that
pmk-3 mutant BAG neurons overexpress insulin-like peptides compared to wild-type BAG neurons. Together, our data suggest that PMK-3 regulates gene expression in developing chemosensory neurons by inhibiting an autocrine insulin-signaling system. Our findings reveal an unexpected role for both neural activity and insulin signaling during neurodevelopment. The mechanisms revealed by our studies will advance our understanding of mechanisms that couple neural activity to neurodifferentiation.