Vitamin A deficiency studies first highlighted the essential role of retinoids in kidney development, since offspring of vitamin A deficient dams exhibit severe renal malformations. The vitamin A metabolite retinoic acid (RA), mediates many vitamin A dependent events both in the embryo and in the adult. The RA signal is transduced by nuclear retinoic acid receptors (RARS), which act as ligand-activatable transcription factors. Vitamin A deficient fetuses and RAR mutants in which multiple RAR proteins have been inactivated, display similar renal abnormalities. The kidneys of RARalphabeta2 mutants are small and ectopically located containing few nephrons and tubules. In addition, RARalphabeta2 mutant metanephroi lack the nephrogenic zone, the outer layer of cells encircling the metanephros, where nephrons are continuously generated. The finding that expression of the RA-synthesizing enzyme, retinaldehyde dehydrogenase-2 is confined to the nephrogenic zone and capsule, supports a model in which RA generated at the periphery of the metanephros is important for maintaining survival and inductive properties of the nephrogenic zone. We hypothesize that expression of RARalpha and RARbeta2 in stromal cells is required of ureteric bud branching and nephrogenesis, and for maintenance of the nephrogenic zone. We will test the hypothesis that RA synthesized in the nephrogenic zone is important for renal development by generating mice in which the RALDH-2 gene is inactivated, using a tetracycline-inducible knockout. We will test whether RAR signaling is required in the stromal compartment, by generating stromal cell lines, and testing their ability to rescue development of the RARalphabeta2 and RALDH-2 mutant metanephroi. Our results suggest that the stromal compartment may be composed of distinct cell types, which may also possess distinct functions. The availability of stromal cell lines will enable us to identify new sub-populations of stromal cells, and to characterize their signaling properties with respect to metanephric development.
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