FUNCTIONS OF GAP-43 BY GENETIC MANIPULATION

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EXCEED THE SPACE PROVIDED. The evolution of functional complexity in the vertebrate CNS has been facilitated in large part by functional divergence within large homologous families of neurogenesis and guidance cues. We therefore need to identify the intracellular mechanisms that have enabled this functional divergence to occur. We have hypothesized that any such mechanisms arising at crucial junctures during evolution of the vertebrate brain will likely play highly important roles in vertebrate-specific functions. The goal of this proposal is to characterize the functions of one candidate, the growth-associated protein GAP-43, during neurogenesis and axon guidance in vivo. GAP-43 first appeared during teleost evolution ~ a critical juncture when continually shifting connections first began to be used as a developmental mechanism. It plays a major role in all aspects of neuronal function. GAP-43 is required for the transduction of cell-adhesion molecule (CAM) mediated signaling in axons and is clearly required for maturation of vertebrate neurons: GAP-43 (-/-) mice die perinatally in association with severe abnormalities of axonal pathfinding that affects map formation in the cortex. In addition, GAP-43 (+/-) mice display an autosomal dominant syndrome of which one major symptom is agenesis of the corpus callosum (ACC). Likewise in humans, deletions of the GAP-43 locus also give rise to an autosomal dominant syndrome that includes ACC. This, together with the essential role of GAP-43 in CAM-mediated signaling, makes it critical to clarify the deficiencies seen in the GAP-43 (-/-) and (+/-) mice. In this proposal we will combine neuroanatomical and immunohistochemical methods in vivo and in vitro to determine how failure to express GAP-43 during neurogenesis and axon outgrowth of cortical pioneer neurons in turn influences organization of thalamortical afferents as they grow into neocortex to establish functional maps. Next we will determine whether defective axon outgrowth of cortical efferents in (+/-) mice with ACC reflects failure of pioneer axons to recognize callosal guidance cues, as well as how haploinsufficiency and penetrance of the (+/-) phenotype is regulated. Finally we will take advantage of a strain of genetically engineered mice to directly examine map formation in olfactory cortex in vivo. The results will address the extent of GAP-43 function during neuronal development in the CNS that, given its haploinsufficiency, may also have consequences on human neurological disorders. 3ERFORMANCE SITE(S) (organization, city, state) Department of Pharmacology SUNY Health Science Center 750, E. Adams St Syracuse, NY 13210 KEY PERSONNEL ========================================Section End===========================================