Vision is arguably one of our most important senses and accounts for much of our behavior. The proper function of the visual system requires highly specific connections between the retina and its central nervous system (CNS) targets which come about as a result of precise axonal guidance during development. Our long term goal is to understand at a molecular level how retinal ganglion cell (RGC) axons navigate within the developing brain and find their way to specific CNS sites. Here, studies will investigate 1) axon guidance cues controlling RGC axon exit from the retina into the optic nerve and 2) growth cone signaling molecules needed for optic tract formation along the lateral wall of the diencephalon. In previous studies we found that in mouse embryos lacking the axon guidance cure netrin-1 at the optic disc, or its receptor DCC on RGC axons, the majority of RGC axons are unable to grow through the optic disc into the optic nerves. Recently, we found that a member of the semaphorin family of axon guidance cues is also expressed at the optic disc in a pattern similar to netrin-1. In the proposed work, we will determine whether this optic disc semaphorin inhibits or promotes RGC axon growth, and use gene targeting strategies to study how elimination of its function affects optic nerve development. The intracellular signaling pathways which underlie axon guidance in vivo are largely unknown. GAP-43 is an intracellular growth cone protein that in vitro interacts via defined domains with signaling intermediates such as PKC, calmodulin, and G proteins and their effectors. RGC axons in GAP-43 deficient embryos are unable to grow from the optic chiasm into the lateral wall of the diencephalon to form the optic tracts. It is not known whether GAP-43 in vivo functions through PKC activation and release of calmodulin or by directly affecting G protein signaling. We will analyze the precise role of these interactions in optic tract development by crossing transgenic animals expressing engineered forms of GAP-43 with GAP-43 deficient mice. The presence of normal optic tracts in animals resulting from such crosses will identify interaction domains necessary for GAP-43 function in vivo. Together, these two sets of proposed studies will further our understanding of the formation of the optic nerve and optic tract; two critical segments of the visual pathway. The results may also provide insight into the etiology of the developmental disorders such as optic nerve hypoplasia and assist in attempts to promote functional recovery in the visual system after injury or disease.
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