Integrins, the principal receptors that mediate cell-ECM interactions, are composed of heterodimeric transmembrane and subunits. The 18 and 8 subunits found in mammals combine in a restricted manner to form specific dimers with different ligand binding properties. 1, the most abundantly expressed integrin subunit in the kidney, binds at least 12 subunits. Its short cytoplasmic tail interacts with multiple intracellular molecules tht promote integrin- mediated adhesion, migration and signaling. The best defined of these proteins are talins and kindlins, which we and others showed are required for normal integrin function. These proteins bind to two canonical NPXY motifs found in all integrin cytoplasmic tails: talins to the membrane proximal and kindlins to the membrane distal motifs. In the last funding period, we utilized integrin beta1flox/flox mice to demonstrate that this integrin subunit s required for normal uretereic bud (UB) development, as deleting it using hoxb7cre mice resulted in severe abnormalities in branching morphogenesis. We further showed that mutating canonical NPXY motifs of the integrin 1 cytoplasmic tail also resulted in abnormal UB development. Kidneys with a Y/A mutation in both motifs (thus affecting binding of talins and kindlins) are severely dysmorphic and dysplastic, but have a significantly less severe branching defect than the UB integrin 1-null mice. Thus a key unanswered question in the field of integrin biology and kidney development is how the NPXY motifs regulate integrin function and whether they have distinct functions from each other. We propose to answer this question by testing the hypothesis that binding of talins and kindlins to specific NPYX motifs of the integrin 1 cytoplasmic tail differentially regulates integrin functions required for normal UB development. This hypothesis will be tested by the following three specific aims. 1) Determine if talin binding to the membrane proximal NPXY motif of the integrin 1 cytoplasmic tail is required for normal UB development. 2) Determine if kindlin binding to the membrane distal NPXY motif of the integrin 1 cytoplasmic tail is required for normal UB development and function. 3) Define the mechanisms whereby integrin 1 NPXY motif binding proteins regulate collecting duct cell branching morphogenesis. Completion of these aims will help define the fundamental mechanisms whereby 1 integrins regulate renal tubule formation in the context of UB development. This has implications for our understanding of both congenital renal hypoplasia/dysplasia syndromes and adult renal diseases as UB branching is a key determinant of nephron number.
We anticipate that this study will generate novel insights into the role of integrins and their binding partners, talins and kindlins in the development of the collecting system of the kidney. This knowledge is fundamental to our understanding of how the renal collecting system functions and could potentially define new etiologies for dysmorphic dysgenic kidneys in infants.
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