CYTOSKELETAL SIGNALING AND AXON GUIDANCE

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DESCRIPTION (From the Applicant's Abstract): The establishment and maintenance of cell shape and polarity play key roles in the development of multicellular organisms. In the developing nervous system, neurons send axons to their correct targets to form an axon scaffold upon which functional neuronal connections are made. How are axons guided to their targets in the nascent nervous system? Recent efforts suggest that extracellular cues provide guidance information and are detected by transmembrane receptors present on the growth cone, the sensory motile structure at the distal tip of an extending axon. In response to such cues, the actin cytoskeleton of the growth cone, which mediates growth cone movement, is altered to achieve directed migration of the growth cone. Many guidance cues and their receptors have been identified. Less is known about the intracellular signaling mechanisms that transmit axon guidance signals to the actin cytoskeleton. The study proposed here aims to identify and characterize cytoplasmic signaling mechanisms that link axon guidance receptors to the actin cytoskeleton in the nematode Caenorhabditis elegans. Mutations in the unc-115 gene cause specific axon guidance and outgrowth errors. Unc-115 encodes a new conserved actin-binding protein that might modulate the actin cytoskeleton in response to axon guidance signals. Unc-115 acts genetically with Rac GTPase signaling and interacts physically with the novel WD-40 repeat protein AXM-1 in axon guidance. The three C. elegans Rac genes, ced-10, mig-2 and rac-2, define three parallel and redundant signaling pathways that mediate axon guidance. Unc-115 acts in the rac-2 pathway and in parallel to mig-2 and ced-10. Possibly, UNC-115 modulates the growth cone actin cytoskeleton in response to guidance cues transmitted through RAC-2 signaling and AXM-1. Experiments described here aim to elucidate the role of unc-115 in axon guidance signal transduction. The first aim is to identify additional genes that act with unc-115 in axon guidance by two means: screening existing candidate mutants for interactions with unc-115; and utilizing the redundancy in Rac gene function to screen for new mutants in the unc-115 pathway by virtue of synthetic axon defects with mig-2. The second aim is to characterize molecules that interact physically with the UNC-115 molecule, including AXM-1. The third aim is to investigate the molecular mechanisms of unc-115 function to elucidate events taking place during signaling to the cytoskeleton in the growth cone.