Exploring the function and shedding of a potential C. elegans Neuregulin - PROJECT SUMMARY/ABSTRACT Signaling by Epidermal Growth Factor (EGF) family ligands through EGFR/ErbB receptors controls myriad developmental and behavioral processes across metazoa and its dysregulation contributes to human diseases such as cancer and schizophrenia. Our understanding of EGF signaling is founded in studies of the nematode C. elegans, which for decades has served as a model for the function of a single ligand–receptor pair, encoded by lin-3/EGF and let-23/EGFR. The central role for EGF signaling in C. elegans vulval organogenesis, along with the powerful molecular-genetic tools available in this model system, has revealed foundational concepts in signal transduction. In recent years an EGFR- dependent sleep state triggered by various forms of cellular damage has been identified in C. elegans. This stress-induced sleep (SIS) has since been observed in Drosophila and zebrafish, and may represent a core constituent of sleep drive. Consistent with this notion, EGF family ligands have been found to have sleep-promoting activity across species including mammals. However, the mechanism by which cellular damage leads to EGFR activation within sleep-promoting neurons is not known. As LIN-3 is the only recognized EGFR ligand in C. elegans, the requirement for LIN-3 in SIS has been largely assumed rather than carefully examined. Further, attempts to identify a protease that releases the soluble EGF domain from its membrane-bound proprotein in response to cellular stress have been unsuccessful. Based on considerable student-gathered data, including findings from unbiased genetic screens for sleepless mutants, we hypothesize that C. elegans possesses an additional EGFR ligand that is processed by a stress-responsive metalloprotease, ADM-4, to trigger sleep. We present a rigorous molecular-genetic research plan involving students that aims to characterize this new EGF family ligand and its sheddase. These studies are expected to demystify the initiation of stress-induced sleep, with potential relevance across species, and establish a powerful genetic model for stress- responsive EGFR activation with relevance to cancer.
