Integrins are transmembrane heterodimeric 1 and 2 subunit glycoproteins that mediate the interactions between cells and extracellular matrix (ECM). In humans there are 18 1 and 8 2 subunits, which combine in a restricted manner to form dimers, each of which exhibit different ligand binding properties. Integrins play a critical role in organ development and morphogenesis as they modulate cell shape, polarity, growth and motility. 21 is the most abundantly expressed integrin subunit in the kidney and can bind at least 12 1 subunits. Its short cytoplasmic tail binds to many cytoplasmic molecules that are important for integrin-mediated signaling and modulation of the cytoskeleton. Although it is clear that 21 integrin is necessary for normal embryogenesis; its specific function in renal development is poorly characterized. Integrin 21-null mice die at the peri-implantation stage, thus making difficult, if not impossible, to analyze the role of this receptor in kidney development. Recent availability of FLOXED 21 integrin mice and mice with CRE-recombinase driven by nephron segment specific promoters now allow us to determine the role of 21 integrin in the development and/or function of specific nephron segments. In addition, with the ability to generate point mutant knock-in mice, it is possible to determine the role of the integrin cytoplasmic tail in organ development and/or function in vivo. The collecting system of the kidney is derived from the ureteric bud (UB) which undergoes repetitive bifid branching events during early development followed by a phase of tubular growth, elongation and differentiation. By crossing FLOXED 21 null and knock-in mice with mice that express cre when UB development commences (hoxb7 cre) or after the majority of branching morphogenesis has occurred (aquaporin2 cre), we will test the hypothesis that 21 integrin is critical for UB branching morphogenesis but is expendable for collecting duct growth, elongation and differentiation.
Aim 1) Determine how loss of integrin 21 in the developing UB affects renal development and function.
Aim 2) Determine the role of the 21 integrin cytoplasmic tail in renal collecting system development.
Aim 3) Determine the mechanism whereby integrin 21 induces renal epithelial cell polarity and branching morphogenesis.Narrative and significance. The studies proposed in this grant application will provide insight into the mechanisms of normal kidney development. In addition, they will investigate the mechanisms whereby children develop abnormalities of the collecting system of the kidney, which is a common cause of end stage renal failure in the pediatric population. ? ? ?
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