Kidney disease is universally characterized by the loss of epithelial integrity, leading to physiological dysfunction with the potential for renal failure. A major common pathway through which epithelial cell damage occurs is by disruption of vital interactions between epithelial cells and their basement membranes. This is observed in polycystic kidney, congenital nephritic syndromes, diabetic nephropathy, and the various forms of glomerulonephritis that lead to the nephritic syndrome. The interaction of epithelial cells with the basement membrane is mediated by integrin receptors for the extracellular matix (ECM). Integrins are expressed on the basal membranes of epithelial cells and are believed to be the major class of receptors adhering cells to the basement membrane. Our studies on mice deficient in alpha3beta1 integrin have indicated that this receptors has important functions during the development of the kidneys, lungs, skin, and brain. By deriving immortalized epithelial cell lines from wild type and alpha3beta1 integrin-deficient collecting ducts, we have established a system for studying how integrins maintain epithelial morphology. In wild type cells a normal cortical cytoskeleton is present. In contrast alpha3beta1 integrin-deficient cells assemle actin stress fibers. Our present results also indicate that alpha3beta1 integrin is required for cadherin:catenin complexes to maintain their association with the cytoskeleton. Our proposed experiments will test the hypothesis that Rho family GTPases act as downstream effectors of alpha3beta1 integrin to mediate cadherin:catenin mediated organization of the cortical cytoskeleton in epithelial cells. We will also test the hypothesis that the pattern of cytoskeletal assembly is determined by the integrin repertoire. These hypotheses will be tested by (1) analyzing downstream effectors of Rho family GTPases in epithelial cell lines from wild type and alpha3beta1 integrin-deficient kidney collecting ducts; (2) Analyzing cadherin:catenin:cytoskeletal interactions in cell lines transfected different with different integrin alpha-subunits; (3) assessing cadherin clustering in wild type and alpha3beta1 integrin-deficient cells, and (4) determining the effects of beta-catenin mutants on cytoskeletal assembly in wild type and alpha3beta1 integrin-deficient cells.
| Liu, Yingjie; Chattopadhyay, Nibedita; Qin, Shan et al. (2009) Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis. Development 136:843-53 |
| Chattopadhyay, Nibedita; Wang, Zemin; Ashman, Leonie K et al. (2003) alpha3beta1 integrin-CD151, a component of the cadherin-catenin complex, regulates PTPmu expression and cell-cell adhesion. J Cell Biol 163:1351-62 |
