MOLECULAR GENETICS OF BASEMENT MEMBRANES IN C ELEGANS

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Basement membranes are specialized extracellular matrix structures, found in all metazoans, that are believed to function in several important developmental processes, including; cell adhesion, cell migration, cell differentiation, and morphogenesis. Basement membranes are also thought to be involved in certain pathologic conditions, such as tumor metastasis, wound healing, blistering diseases of the skin, and certain forms of nephritis. Knowledge of the functions of basement membranes has been derived primarily from studies of purified basement membrane components, no genetic studies of basement membrane function have been performed. One of the most abundant and ubiquitous components of basement membranes is the basement membrane-specific type IV collagen. The recent identification of mutations in the genes that encode the two type IV collagen chains in the nematode Caenorhabditis elegans provides the first opportunity for genetic analyses of basement membrane functions. The aim of this application is to pursue both genetic and molecular analyses of basement membrane structure and function in C. elegans. The powerful genetic and molecular analyses that are possible in C. elegans, and its simple, well defined anatomy, make it an excellent system for studying the structure and functions of basement membranes. Multiple independent mutations in the type IV collagen genes will be generated and their effects on the development of C. elegans will be determined by a combination of microscopic and molecular analyses. the nucleotide and amino acid sequence alterations caused by these mutations will be determined and will provide value information towards defining functionally important regions of the type IV collagen molecule. Genetic loci that interact with the type IV collagen genes will be identified, since they are likely to encode other basement membrane components. Such interacting loci may encode known basement membrane components, such as laminin, entactin, or the heparan sulfate proteoglycan core protein, or could encode previously unidentified components of basement membranes. Mutational analyses of interacting loci will also define the regions within different proteins that physically interact loci will also define the regions within different proteins that physically interact to form basement membranes. The genetic analyses possible in C. elegans will provide a better understanding of both the structure and functions of basement membranes.