The long-term goal of this research is to understand molecular mechanisms underlying neuronal differentiation and the formation of specific neuronal connections in the visual system. The objective of the proposed studies is to determine the roles of cadherin molecules in regulating neurite outgrowth and axonal pathfinding of retinal ganglion cells in developing zebrafish. Cadherins are Ca-dependent cell adhesion molecules that have been demonstrated to play critical roles in cell differentiation and tissue formation. Both in vitro and in vivo studies using a variety of vertebrate species have shown that cadherins are involved in retinal axon fasciculation, axonal outgrowth and pathfinding, retinotectalsynaptic formation and stabilization. However, most of the studies to date have focused on N-cadherin, and there is relatively little information on the role(s), and in particular the in vivo functions, of other cadherins, in these processes. Moreover, little is known about relative roles of different cadherin molecules in the development of retinal ganglion cells. I propose to study the expression patterns and functions of both R- and N-cadherins in the visual system of developing zebrafish. This proposal has three specific aims: A) to generate neutralizing antibodies, B) to further characterize the expression patterns of R- and N-cadherins, and C) to assess the relative roles of R- and N-cadherins by application of neutralizing antibodies to the eye and optic pathway, and application of dominant negative constructs to the eye. The proposed studies, designed to uncover mechanisms underlying retinal ganglion cell differentiation, outgrowth and pathfinding of their axons, may provide insights into therapies for injured or congenitally defective human retinal and optic nerve tissues.
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