STRUCTURE AND FUNCTION OF NON BASEMENT MEMBRANE LAMININS

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A novel laminin subunit chain, gamma3, has been recently identified. Biochemical studies of gamma3 containing laminins show that gamma3 can associate with at least alpha2, alpha4, beta1, and beta2 subunit chains. The tissue distribution of gamma3 shows it to be present in regions not containing ultrastructurally defined basement membranes. These regions include the brain matrix and the apical surface of ciliated epithelial cells. The following specific aims describe proposed intentions to test the hypothesis that gamma3 containing laminins form a unique matrix at these non-basement membrane sites, the function of which is to stabilize the cytoskeletal arrangements required for the assembly and stabilization of cilia, and to also provide a distensible matrix stabilizing the structure of the CNS. To test this hypothesis specific aims are proposed: (1) Carefully describe the anatomical distribution of gamma3 and other selected laminin chains, as well as of known matrix macromolecules and receptors in the brain and at ciliated epithelial surfaces during development and in the adult mouse; (2) Determine the molecular composition of gamma3 containing laminins in the brain and at ciliated epithelial surfaces. Chemical quantities of the appropriate laminins will be produced in cell culture and purified. (3) Potential interactions between molecules which colocalized spatially and temporally will be tested in vitro. Binding to potential receptors will be determined by cell binding studies. (4) A gamma3 null mouse will be generated by homologous recombination and the phenotype characterized. We will cross the gamma3 and beta2 heterozygous mice to produce the double KO. It is likely that these studies will provide the foundations for further study of a novel extracellular matrix. It is also possible that these studies will provide novel insights into the pathophysiology of neurodegenerative diseases and infertility.