The cadherins are Ca2+ dependent cell adhesion molecules important for the biogenesis of polarized epithelia and for the morphogenesis of epithelial tissues during embryonic development. The long term objectives of this research are to elucidate the cellular and molecular mechanisms of cadherin function, to understand how cadherins participate in the biogenesis of epithelia, and to determine how changes in the expression of different cadherin types contribute to the morphogenesis of epithelial tissues. The functions of cadherins in these processes entail both specific intercellular recognition events, mediated by their extracellular domains, and interactions with elements of the cytoskeleton, through their cytoplasmic domains. To begin to investigate the nature of the molecular interactions between cadherins and the cytoskeleton, a cDNA encoding a 92 kD protein (a """"""""catenin"""""""") that binds tightly to the cytoplasmic tail of E-cadherin will be cloned and sequenced. This cDNA clone will be used to characterize the 92 kD protein and to investigate its function in cell adhesion and epithelial biogenesis. The early developing embryo of the amphibian Xenopus laevis will be used as a model to investigate the functions of cadherins in the biogenesis and morphogenesis of epithelial tissues. The major, if not only, cadherin expressed during the cleavage and blastula stages has been named """"""""C-cadherin"""""""". Its role in cleavage, adhesion between blastomeres, and the biogenesis of the blastula, an embryonic epithelium, will be investigated by manipulating its expression and/or function in vivo. The rapidly cleaving embryos also will be used to analyze the assembly of cadherin-mediated cell contacts. In particular, the biogenesis of the cleavage furrow membrane, in which both adhesive and nonadhesive domains can be distinguished morphologically, will be examined. The expression of the prototypical epithelial cadherin, E-cadherin, in Xenopus occurs in association with the morphogenesis of the ectodermal cell layer during gastrulation. The significance of E-cadherin expression for the development of the ectodermal epithelium will be explored. The consequences of E-cadherin misexpression in cultured embryonic cells or tissues and in whole embryos will be analyzed using functional assays for the known properties of epithelia. Serious health problems result from disruptions in the epithelia of many organ systems like the gastrointestinal tract, the kidney, and the lungs. The proposed studies will contribute to understanding the mechanisms of epithelial healing and repair. Moreover, learning about the functions of the cadherins in morphogenesis may offer insights into the origins of birth defects or other reproductive problems.
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