Deletion of Frs2α from the ureteric epithelium causes renal hypoplasia

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

Research output: Contribution to journalArticle

29 Scopus citations

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 2α (Frs2α) is a major docking protein for Fgfr2 with downstream targets including Ets variant (Etv) 4 and Etv5 in other systems. Furthermore, global deletion of Frs2α causes early embryonic lethality. The purpose of the study was to determine the role of Frs2α in mediating Fgfr2 signaling in the ureteric epithelium. To that end, we generated mice with conditional deletion of Frs2α in the ureteric epithelium (Frs2αUB-/-) and mice with point mutations in the Frs2α binding site of Fgfr2 (Fgfr2LR/LR). Frs2αUB-/- 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 Fgfr2LR/LR mice. Interestingly, Etv4 and Etv5 expression was unaltered in Frs2αUB-/- mice, as was Sprouty1, an antagonist of Frs2α 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 Frs2α in the ureteric epithelium. Furthermore, Frs2α may transmit signals through other receptor kinases present in ureteric epithelium. Finally, the renal hypoplasia observed in Frs2αUB-/- mice is likely secondary to decreased Ret and Wnt11 expression.

Original languageEnglish (US)
Pages (from-to)F1208-F1219
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number5
DOIs
StatePublished - Nov 2009
Externally publishedYes

Keywords

  • Conditional knockout
  • Fibroblast growth factor receptor 2
  • Fibroblast growth factor receptor substrate 2
  • Kidney development; branching morphogenesis

ASJC Scopus subject areas

  • Physiology
  • Urology

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