The overall objective of this project is to obtain a more detailed description of the role of cell-cell interactions in the development of the eye. Our primary focus is the neural cell adhesion molecule (NCAM), which is abundantly expressed in the eye and believed to influence a variety of developmental events. The studies also lead to the evaluation of other CAMs, gap junctions and adherens junctions. The emphasis is on two areas: the neural retina, in particular the formation of the ganglion cell and optic fiber layers, and the lens, where the interrelationship of NCAM and specialized junctions will be evaluated. Several experimental systems will be used, including in vitro models for analyzing adhesive choices in the retina and mechanisms of lens morphogenesis and differentiation, specific molecular perturbation of both tissues in vivo using antibodies and enzymes, and the analysis of mice that have site-directed mutations in NCAM. The following specific aims are proposed: Use an assay for adhesive choices made by axons and glial cells to investigate the molecular mechanisms underlying formation of the optic fiber layer and optic nerve, 2) Continue our in vivo studies on the cellular and molecular events that lead to localization of ganglion cells at the vitreal margin of the retina and the initial appearance of axons at that site, 3) Test our hypothesis that the role of NCAM in lens formation includes promotion of gap junction and adherens junction formation, and 4) Use mutations that restrict expression of particular structural forms of NCAM to further refine our understanding of the mechanisms by which this molecule influences eye development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006107-07
Application #
3262093
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1986-01-01
Project End
1995-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ono, K; Tomasiewicz, H; Magnuson, T et al. (1994) N-CAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid. Neuron 13:595-609
Yang, P; Major, D; Rutishauser, U (1994) Role of charge and hydration in effects of polysialic acid on molecular interactions on and between cell membranes. J Biol Chem 269:23039-44
Tomasiewicz, H; Ono, K; Yee, D et al. (1993) Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 11:1163-74
Yang, P; Yin, X; Rutishauser, U (1992) Intercellular space is affected by the polysialic acid content of NCAM. J Cell Biol 116:1487-96
Zhang, H; Miller, R H; Rutishauser, U (1992) Polysialic acid is required for optimal growth of axons on a neuronal substrate. J Neurosci 12:3107-14
Rao, Y; Wu, X F; Gariepy, J et al. (1992) Identification of a peptide sequence involved in homophilic binding in the neural cell adhesion molecule NCAM. J Cell Biol 118:937-49
Cervello, M; Lemmon, V; Landreth, G et al. (1991) Phosphorylation-dependent regulation of axon fasciculation. Proc Natl Acad Sci U S A 88:10548-52
Watanabe, M; Rutishauser, U; Silver, J (1991) Formation of the retinal ganglion cell and optic fiber layers. J Neurobiol 22:85-96
Hall, A K; Nelson, R; Rutishauser, U (1990) Binding properties of detergent-solubilized NCAM. J Cell Biol 110:817-24
Watanabe, M; Kobayashi, H; Rutishauser, U et al. (1989) NCAM in the differentiation of embryonic lens tissue. Dev Biol 135:414-23

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