The development of the central nervous system requires the precise control of axon outgrowth. This outgrowth is primarily achieved by a highly motile, actin-rich structure at the tips of axons, called the axon growth cone. The growth cone is highly responsive to extracellular cues, which are transduced by finger-like protrusions called filopodia. These cues drive rearrangement of the actin cytoskeleton to produce specific growth cone behaviors. While much is known about guidance cues and their receptors, the pathways by which cues drive cytoskeletal rearrangement are not well understood. LIM and SH3 Protein 1 (LASP1) is a unique actin-binding protein that contains multiple protein interaction domains and several phosphorylation sites, thus may function to mediate complex signaling pathways to regulate actin dynamics. The LASP1 gene is implicated in autism and schizophrenia, and LASP1 expression is correlated with cellular motility of many types of cancer cells. Within the brain, LASP1 has been shown to be highly expressed in the growth cone during development. Our preliminary data indicate that LASP1 localizes to the leading edge of growth cones, which is known to be the site of actin polymerization and protrusion. However, the role of LASP1 in actin dynamics and growth cone behaviors are not well understood. Given that LASP1 expression levels positively correlate with actin-based cellular motility, and that LASP1 has been shown to be essential for chemokine-directed motility of immune cells, I hypothesize that LASP1 promotes actin polymerization downstream of axon guidance cues in the growth cone. I will test this hypothesis using high resolution microscopy and molecular approaches, in both in vivo and in vitro models. Specifically, I propose to complete experiments that examine the role of LASP1 function at the leading edge, as well as its function in axonal outgrowth, guidance, and branching. Completion of these experiments will elucidate the mechanism of LASP1 in actin-based motility as well as neurological disease and cancer metastasis.
The development of a fully functional brain requires appropriate cue-dependent axon guidance and actin regulation. Defects in brain development can result in a variety of neurological diseases. This study will focus on the communication of axon guidance cues to the actin cytoskeleton, and how guidance is disrupted when proteins in the signaling pathways are altered.
