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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/F1208    most recent 00262.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sims-Lucas, S. Articles by Bates, C. M. PubMed PubMed Citation Articles by Sims-Lucas, S. Articles by Bates, C. M.

Deletion of Frs2 from the ureteric epithelium causes renal hypoplasia

¹Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh; ; ²Center for Cell and Developmental Biology, The Research Institute at Nationwide Children's Hospital, Columbus; ; ³Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; ; ⁴Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut; ; ⁵Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M, Houston, Texas; ; ⁶Division of Nephrology, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio; and ; ⁷Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted May 11, 2009 ; accepted in final form September 7, 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 (Frs2) 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 causes early embryonic lethality. The purpose of the study was to determine the role of Frs2 in mediating Fgfr2 signaling in the ureteric epithelium. To that end, we generated mice with conditional deletion of Frs2 in the ureteric epithelium (Frs2^UB–/–) and mice with point mutations in the Frs2 binding site of Fgfr2 (Fgfr2^LR/LR). Frs2^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^UB–/– mice, as was Sprouty1, an antagonist of Frs2 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 in the ureteric epithelium. Furthermore, Frs2 may transmit signals through other receptor kinases present in ureteric epithelium. Finally, the renal hypoplasia observed in Frs2^UB–/– mice is likely secondary to decreased Ret and Wnt11 expression.

fibroblast growth factor receptor substrate 2; fibroblast growth factor receptor 2; kidney development; branching morphogenesis; conditional knockout