title: Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia.
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 2alpha (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 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 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 vs. 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.
authors.affiliation: Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15201, USA.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.forename: Luise
authors.initials: L
authors.lastname: Cullen-McEwen
authors.forename: Veraragavan P
authors.initials: VP
authors.lastname: Eswarakumar
authors.forename: David
authors.initials: D
authors.lastname: Hains
authors.forename: Kayle
authors.initials: K
authors.lastname: Kish
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Jue
authors.initials: J
authors.lastname: Zhang
authors.forename: John F
authors.initials: JF
authors.lastname: Bertram
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Carlton M
authors.initials: CM
authors.lastname: Bates
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D004848:Epithelium / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005838:Genotype; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000254:growth & development / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000033:anatomy & histology / Q000502:physiology; D009924:Organ Culture Techniques; D009929:Organ Size; D017354:Point Mutation / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014513:Ureter / Q000473:pathology*
chemical_list: C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D016222:Fibroblast Growth Factor 2