Non-canonical mechanisms of Toll-like receptor function in the chemosensory nervous system

PROJECT SUMMARY Toll-like receptors (TLRs) are an evolutionarily ancient class of cell-surface molecules with well characterized roles in morphogen signaling and innate immunity. In these contexts, TLRs use a canonical signaling mechanism that involves recruitment of adapter proteins to the cytoplasmic domain of TLRs and subsequent activation of a kinase cascade that regulates transcriptional responses. Recently, we and others have found that TLRs are required for normal development and function of sensory circuits. Unlike morphogen signaling and innate immunity, sensory circuit development does not require canonical TLR signaling mechanisms. The non-canonical mechanisms by which TLRs regulate the development of sensory circuits are unknown. I propose studies of the sole TLR encoded by the C. elegans genome, TOL-1, to reveal how non- canonical TLR signaling regulates sensory system development and function and to identify molecular mechanisms of non-canonical TLR signaling. My preliminary data show that TOL-1 is highly enriched in in the developing neuropil of embryonic nervous system. Using a genetically engineered conditional allele of tol-1, I found that depletion of TOL-1/TLR from sensory neurons causes marked defects in chemotaxis behavior. My preliminary data further show that TOL-1 does not require its intracellular domain to function in sensory neurons, indicating that its function is independent of canonical TLR signaling mechanisms. l will use C. elegans genetics, genomics, and high resolution / super-resolution microscopy to (1) determine how TLRs regulate the establishment and maintenance of sensory neuron architecture and function, (2) test the hypothesis that TLRs that lack the ability to directly interact with intracellular partners are nevertheless able to regulate gene expression in sensory neurons, and (3) test the hypothesis that TLR function in sensory neurons requires interactions with specific extracellular partners. The proposed studies will advance understanding of how a highly conserved family of cell-surface receptors functions in sensory circuits.