Mechanisms of gene regulation by an E3 ubiquitin ligase during neurodevelopment

Project Summary During development, fixed genetic programs generate the neuronal diversity required for the complex circuits that generate and modulate behavior. Other developmental mechanisms work in tandem with these fixed programs and regulate gene expression in response to neuronal activity and other extrinsic cues. How these different developmental processes are controlled and coordinated during neurodevelopment remains a major question. The nematode C. elegans is a powerful model for the study of neurodevelopment, as most C. elegans neurons quickly assemble into circuits during embryogenesis. By using C. elegans we can (1) observe neurodevelopment in real time, (2) deploy powerful genetic and genomic tools, and (3) observe the consequences of genetic manipulations on nervous system structure and function. This project will focus on the development of a pair of C. elegans chemosensory neurons, the BAGs, which control behavioral responses to aversive cues in the environment. Prior studies revealed an unexpected role for the p38 MAP kinase PMK-3 during a critical period in embryonic development when BAG neurons establish expression of genes required for their function. Neural activity during this critical period also influences BAG neuron development. To determine how PMK-3 regulates gene expression during neurodevelopment, we performed a genetic screen for modifiers of the gene expression and functional defects caused by mutation of PMK-3. Through fine mapping a suppressor mutation, I identified the highly conserved E3 ubiquitin ligase HECD-1 as a factor that acts either downstream of or in parallel to p38 MAPK. The proposed research plan will determine the mechanism by which HECD-1 regulates gene expression during nervous system development. Because mutation of the human homolog of HECD-1 has recently been linked to severe neurodevelopmental disorders, these studies will advance understanding of molecular mechanisms that go awry in neurodevelopment to cause disease.