Related Experiment Videos
Stromal cells mediate retinoid-dependent functions essential for renal development
C Mendelsohn1, E Batourina, S Fung
1Columbia University, Department of Urology, New York, NY 10032, USA. clm20@columbia.edu
Abstract:
The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(-) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(-) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(-) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression 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 ureteric bud branching in RARalpha beta2(-) mutants.
Insights
Retinoic acid receptors alpha and beta2 are crucial for embryonic kidney development. Their combined absence impairs ureteric bud branching by downregulating c-ret signaling in stromal cells, leading to renal malformations.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Vitamin A metabolites, retinoids, are essential for kidney development.
- Retinoids signal through retinoic acid receptors (RARs) and retinoid X receptors (RXRs).
- Previous studies indicated RARalpha and RARbeta2 receptors are vital for renal morphogenesis.
Purpose of the Study:
- To investigate the specific roles of RARalpha and RARbeta2 in embryonic kidney development.
- To elucidate the cellular localization and functional interactions of RARalpha and RARbeta2 in the developing kidney.
Main Methods:
- Gene targeting to create RARalpha beta2 double knockout mice.
- Histological analysis of embryonic kidneys.
- Immunohistochemistry to determine receptor localization.
- Gene expression analysis of key developmental markers.
Main Results:
- RARalpha and RARbeta2 are co-localized in embryonic kidney stromal cells.
- RARalpha beta2 mutant kidneys exhibit impaired ureteric bud branching and collecting duct development.
- Nephron formation is unaffected, but ureteric bud tips are abnormally positioned.
- Downregulation of the proto-oncogene c-ret was observed in mutant kidneys.
Conclusions:
- RARalpha and RARbeta2 in stromal cells are essential for maintaining c-ret expression.
- This stromal cell-mediated c-ret signaling is critical for proper ureteric bud morphogenesis.
- Disruption of this pathway leads to renal malformations due to impaired branching.