An area of intense interest in neurobiology is to understand the molecular basis for axon guidance and targeting. Genetic, biochemical and cell biological approaches have lent considerable insight into the relevant underpinnings to these phenomena. The Poo and Tessier-Lavigne lab have provided insight into the molecular details of netrin-1 (N1) and rMAG induced chemotropism in spinal neurons. Recently, they reported that N1 and rMAG mediated attraction or repulsion, respectively, required both the cAMP and Ca2+ signaling pathways. However, the precise details of how cAMP and Ca2+ promote attractive or repulsive responses in growth cones are unknown. This proposal focuses on the downstream events after DCC or MAG receptor occupancy during neurite reorientation toward gradients of N1 or rMAG. It is possible that gradients of cAMP and Ca2+ are established in the cytoplasm in response to external gradients of N1 or rMAG and asymmetrically modify the cytoskeleton to reorient the growth cone toward or away from a guidance cue source. This study will examine the causal relationship between the AMP and Ca2+ pathways with respect to cytoskeletal rearrangement. Furthermore, it will determine if intracellular gradients of PI3 kinase activity are involved. This study could provide insights into the development of better approaches for treating spinal cord or peripheral nerve damage after injury.
