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. This proposal involves mechanisms of axonal pathfinding to their targets in the nascent nervous system. 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. Our studies in Caenorhabditis elegans have revealed that three Rac GTPases define three redundant cytoskeletal signaling pathways in axon pathfinding, and that the GTP exchange factor UNC-73 Trio controls all three pathways. We have found that the actin-binding protein UNC-115 acts downstream of one of the three Rac pathways, possibly to directly modulate actin structure in response to Rac signaling. Further, we have identified a novel Rac regulator, the 7-WD repeat protein SWR-1, which directly binds to both UNC-115 and Racs and represses Rac activity in neuronal morphogenesis. Experiments described here aim to elucidate the role of Rac signal transduction in axon pathfinding, including identification and characterization of new molecules in Rac signaling and analyses of how these molecules relate to one another in axon pathfinding.
The first aim i s to characterize the role of the novel DAD domain in the function of the downstream Rac cytoskeletal effector UNC-115 in axon pathfinding.
The second aim i s to determine the molecular mechanisms of Rac repression by the Rac negative regulator SWR-1.
The third aim i s to identify and characterize new molecules and interactions with Rac signaling by exploiting the redundancy of Rac function in axon pathfinding. Understanding the molecular mechanisms of cytoskeletal signaling could prove critical for developing therapies aimed at mitigating the effects of central nervous system trauma (e.g. spinal cord injury and stroke) as well as tumor metastasis
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