Deletion of Frs2α from the ureteric epithelium causes renal hypoplasia

Sims-Lucas S, Cullen-McEwen L, Eswarakumar VP, Hains D, Kish K, Becknell B, Zhang J, Bertram JF, Wang F, Bates CM. Deletion of Frs2 alpha from the ureteric epithelium causes renal hypoplasia. Am J Physiol Renal Physiol 297: F1208-F1219, 2009. First published September 9, 2009; doi: 10.1152/ajprenal.00262.2009.-Fibroblast growth factor receptor 2 (Fgfr2) signaling is critical in maintaining ureteric branching architecture and mesenchymal stromal morphogenesis in the kidney. Fibroblast growth factor receptor substrate 2 alpha (Frs2 alpha) is a major docking protein for Fgfr2 with downstream targets including Ets variant (Etv) 4 and Etv5 in other systems. Furthermore, global deletion of Frs2 alpha causes early embryonic lethality. The purpose of the study was to determine the role of Frs2 alpha in mediating Fgfr2 signaling in the ureteric epithelium. To that end, we generated mice with conditional deletion of Frs2 alpha in the ureteric epithelium (Frs2 alpha(UB-/-)) and mice with point mutations in the Frs2 alpha binding site of Fgfr2 (Fgfr2(LR/LR)). Frs2 alpha(UB-/-) mice developed mild renal hypoplasia characterized by decreased ureteric branching morphogenesis but maintained normal overall branching architecture and had normal mesenchymal stromal development. Reduced nephron endowment in postnatal mutant mice was observed, corresponding with the reduction in branching morphogenesis. Furthermore, there were no apparent renal abnormalities in Fgfr2(LR/LR) mice. Interestingly, Etv4 and Etv5 expression was unaltered in Frs2 alpha(UB-/-) mice, as was Sprouty1, an antagonist of Frs2 alpha signaling. However, Ret and Wnt11 (molecules critical for ureteric branching morphogenesis) mRNA levels were lower in mutants vs. controls. Taken together, these findings suggest that Fgfr2 signals through adapter molecules other than Frs2 alpha in the ureteric epithelium. Furthermore, Frs2 alpha may transmit signals through other receptor kinases present in ureteric epithelium. Finally, the renal hypoplasia observed in Frs2 alpha(UB-/-) mice is likely secondary to decreased Ret and Wnt11 expression.