Molecular Events in Urogenital Development

Columbia University Health Sciences, New York NY

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Abstract

PROJECT SUMMARY (See instructions): Vitamin A is required for formation of most organs and tissues. Our studies have been focused on urogenital tract abnormalities which are among the most common birth defects in humans. We have shown that RA is required at multiple stages of urogenital tract formation, in the kidney for branching morphogenesis and in the common nephric duct for ureter transposition. In both, RA acts by inducing expression of Ret in epithelial cells that undergo distinct types of remodeling. Our recent studies reveal additional requirements for RA during nephric duct formation and during colelcting duct elongation. We have recently generated a new mouse model in which a dominant negative retinoic acid receptor has been inserted into the Rosa26 locus following a STOP sequence. Expression of this mutant RA-receptor generates a blockade of RA signaling in cells expressing Cre recombinase, enabling cell type-and temporally controlled inhibition of RA signaling. We will use this mouse line in Aim 1, to identify the mechanism by which RA regulates Ret transcription; selectively inactivating RA-receptor mediated signaling in the ureteric bud, renal stroma and nephrogenic mesenchyme. We will study the normal mechanism by which the nephric ducts insert into the primitive bladder in Aim2 and we willi identify the role of Vitamin A in this process. Our analysis of mutants lacking Raldh2, the major RA synthesizing enzyme reveals abnormalities at late developmental stages in tubule extension and a novel domain of Raldh2 expression at the cortico-medullary junction where local proliferation and oriented mitosis occur during papilla formation, suggesting that RA may be important for these processes. We will characterize the role of RA during prenatal and postnatal stages of papilla formation in Aim3 by expressing the dominant negative Rar receptor in the papilla and we will then analyze the effects on tubule extension and oriented mitosis. In addition to identifying potentially new and important roles for vitamin A during development, our studies should help elucidate the molecular and cellular basis of urogenital tract birth defects so that they can one day be treated or prevented.