The development of the retina required a complex interplay between retinal cells and the external molecular and cellular cues that regulate their development. The molecular basis of cell-cell interactions in the retina is poorly understood. Insight into these interactions may lead to treatments aimed at regenerating optic nerve function after injury and to a greater understanding of retinal disease resulting from aberrant cell adhesion events. Preliminary results in this proposal describe evidence that an important cell adhesion receptor subunit, previously thought to act only in blood cells, is expressed in developing retina. The presence of this subunit, called integrin alpha 4, suggests that a novel retinal mechanism for cell-cell interactions may be in operations during retinal development. This proposal addresses the function of alpha4 integrins in retinal development. Integrins are a family of transmembrane, heterodimeric proteins that acts as receptors for a broad range of extracellular matrix and cell surface glycoproteins. In lymphocytes and leukocytes, alpha4 integrins acts as bifunctional receptors for both classes of ligand: they mediate cell attachment to a domain in fibronectin and to the vascular cell adhesion molecule VCAM-1. Since fibronectin has not been consistently detected in developing retina, alpha4 may mediate interactions with VCAM-1 or a novel ligand. The first specific aims of this proposal are to determine the range of retinal cells that express alpha4 integrins and VCAM-1. Next, experiments are proposed to define the functions of alpha4 and VCAM-1 in vitro, using function blocking antibodies to perturb cell adhesion and neurite outgrowth. Finally, in vivo experiments are proposed to alter alpha4 expression, by expressing antisense RNA, and to block alpha4 function, by introducing blocking antibodies to define the role of alpha4 integrins in retinal development.
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