DEVELOPMENT OF PATTERNED VISUAL CONNECTIONS IN THE BRAIN

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DESCRIPTION (from applicant's abstract): Axons of retinal ganglion cells connect to cells in the visual centers of the brain in a precise, stereotypical pattern. This pattern of connections is essential for normal visual function. The goal of this project is to further our understanding of how the proper pattern of connections develops between retinal axons and the central visual centers. This project is guided by the hypothesis that the pattern of retinal connections in the brain is established in part due to a set of cytochemical positional labels carried by the retinal axons and by cells in the target centers to which the axons connect. This project is a continuing effort by this laboratory to identify these positional labels. Available evidence suggests that gradients of specific Eph receptor tyrosine kinases expressed across the retina could be involved in detecting positional labels in the central visual centers. The role of these receptors in development of the visual system has never been directly tested. The overall aim of this project is to determine the role of members of the Eph subfamily of receptor tyrosine kinases in the development of the normal pattern of retinotectal connections. The general approach to this project is to alter the expression by retinal cells of specific receptors and then study the resulting pattern of retinotectal connections in developing chick embryos. The first specific aim is to reduce expression of Cek4, an Eph receptor tyrosine kinase, in the developing retina, and then characterize the effect this has on the pattern of retinotectal connections. Cek4 is normally expressed in a nasal-temporal gradient in the developing retina. Antisense oligonucleotides to Cek4 or control sequences will be injected into the developing retina. The second specific aim is to misexpress Cek4 on the nasal side of the developing retina and then characterize the effect this has on the pattern of retinotectal connections. Retroviruses carrying the Cek4 gene or control sequences will be injected into the nasal side of the developing retina. The third specific aim is to determine if altered expression of Cek4 in the retina changes the nature of the interactions between retinal axons and tectal neurons or nonneuronal cells. The interaction between axons and tectal cells will be observed in tissue culture. The fourth specific aim is to study the effect of altering expression of other Eph receptor protein tyrosine kinases on the pattern of retinotectal connections using approaches similar to those described for Cek4. Initial work will focus on Cek5, which is expressed in a dorsal-ventral gradient in the developing retina.