The extracellular matrix plays a vital role in the normal function of complex organisms. It is implicated in organogenesis, cell differentiation, metastasis, neuronal guidance, wound healing, and protective functions. A specialized sheet-like structure of the extracellular matrix, the basement membrane, underlies various tissues and is in intimate contact with the plasma membrane of the overlying cells. The major components of this structure are laminin, type IV collagen, perlecan and entactin/nidogen. This proposal addresses the biological functions of entactin as a major component of the basement membrane. Entactin is a sulfated glycoprotein consisting of 1217 amino acid residues. The molecule is organized into structural and functional domains that are engaged in interactions with laminin, collagen IV, fibronectin, perlecan, fibulin and fibrinogen. A major junction of entactin is believed to be the organization and stabilization of the basement membrane. In addition, entactin and peptides derived from entactin enhance the attachment and spreading of several types of cells and promote both chemotaxis and phagocytosis in neutrophils. The inactivation of the entactin gene results in an embryonic lethal phenotype in the mouse. It is the purpose of this project to extend the studies on the role that entactin plays in mouse embryogenesis, organ development, and maintenance of tissue functions. In these studies mutations in specific regions of the entactin gene will be introduced into mice by means of modified embryonic stem cells. These efforts will be complemented with experiments to inactivate the gene for entactin in specific tissues by the cre recombinase/loxP system. The embryos and tissues of the mutant animals will be analyzed to correlate the mutations in entactin with tissue morphology and function. It is hoped that the results obtained will contribute to our understanding of basal lamina function at the molecular level in normal development and in pathological conditions.
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