Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia

Sunder Sims-Lucas, Luise Anne Cullen-McEwen, Veraragavan P Eswarakumar, David Hains, Kayle Kish, Brian Becknell, Jue Zhang, John Frederick Bertram, Fen Wang, Carlton M Bates

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

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 (Frs2alpha) is a major docking protein for Fgfr2 with downstream targets including Ets variant (Etv) 4 and Etv5 in other systems. Furthermore, global deletion of Frs2alpha causes early embryonic lethality. The purpose of the study was to determine the role of Frs2alpha in mediating Fgfr2 signaling in the ureteric epithelium. To that end, we generated mice with conditional deletion of Frs2alpha in the ureteric epithelium (Frs2alpha(UB-/-)) and mice with point mutations in the Frs2alpha binding site of Fgfr2 (Fgfr2(LR/LR)). Frs2alpha(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 post-natal 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, Etv5 expression was unaltered in Frs2alpha(UB-/-) mice, as was Sprouty1, an antagonist of Frs2alpha signaling. However, Ret and Wnt11 (molecules critical for ureteric branching morphogenesis) mRNA levels were lower in mutants versus controls. Taken together these findings suggest that Fgfr2 signals through adapter molecules other than Frs2alpha in the ureteric epithelium. Furthermore, Frs2alpha may transmit signals through other receptor kinases present in ureteric epithelium. Finally the renal hypoplasia observed in Frs2alpha(UB-/-) mice is likely secondary to decreased Ret and Wnt11 expression. Key words: fibroblast growth factor receptor substrate 2, fibroblast growth factor receptor 2, kidney development, branching morphogenesis.
Original languageEnglish
Pages (from-to)F1208 - F1219
Number of pages12
JournalAmerican Journal of Physiology-Renal Physiology
Volume297
Issue number5
DOIs
Publication statusPublished - 2009

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