Stromal cells mediate retinoid-dependent functions essential for renal development

The essential role of vitamin A and its metabolites, retinoids, in kidney d evelopment has been demonstrated in vitamin A deficiency and gene targeting studies, Retinoids signal via nuclear transcription factors belonging to t he retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Ina ctivation of RAR alpha and RAR beta 2 receptors together, but not singly, r esulted in renal malformations, suggesting that within a given renal cell t ype, their concerted function is required for renal morphogenesis, At birth , RARa beta 2(-) mutants displayed small kidneys, containing few ureteric b ud branches, reduced numbers of nephrons and lacking the nephrogenic zone w here new nephrons are continuously added. These observations have prompted us to investigate the role of RAR alpha and RAR beta 2 in renal development in detail. We have found that within the embryonic kidney, RARa and RAR be ta 2 are colocalized in stromal cells, but not in other renal cell types, s uggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RAR alpha beta 2(-) mutant kidneys at e mbryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for differen t metanephric mesenchymal cell types. In contrast the development of the co llecting duct system was greatly impaired in RAR alpha beta 2(-) mutant kid neys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of ge nes important for ureteric bud morphogenesis revealed that the proto-oncoge ne c-ret was downregulated. Our results suggest that RARa and RAR beta 2 ar e required for generating stromal cell signals that maintain c-ret expressi on in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired u reteric bud branching in RAR alpha beta 2(-) mutants.