title: Fibroblast growth factor receptor-Frs2α signaling is critical for nephron progenitors.
abstract: Previous studies using transgenic Pax3cre mice have revealed roles for fibroblast growth factor receptors (Fgfrs) and Fgfr substrate 2α (Frs2α) signaling in early metanephric mesenchyme patterning and in ureteric morphogenesis. The role of Fgfr/Frs2α signaling in nephron progenitors is unknown. Thus, we generated mouse models using BAC transgenic Six2EGFPcre (Six2cre) mediated deletion of Fgfrs and/or Frs2α in nephron progenitors. Six2cre mediated deletion of Fgfr1 or Fgfr2 alone led to no obvious kidney defects. Six2creFgfr1(flox/flox)Fgfr2(flox/flox) (Fgfr1/2(NP-/-)) mice generate a discernable kidney; however, they develop nephron progenitor depletion starting at embryonic day 12.5 (E12.5) and later demonstrate severe cystic dysplasia. To determine the role of Frs2α signaling downstream of Fgfr2 in Fgfr1/2(NP-/-) mice, we generated Six2cre(,)Fgfr1(flox/flox)Fgfr2(LR/LR) (Fgfr1(NP-/-)Fgfr2(LR/LR)) mice that have point mutations in the Frs2α binding site of Fgfr2. Like Fgfr1/2(NP-/-) mice, Fgfr1(NP-/-)Fgfr2(LR/LR) develop nephron progenitor depletion, but it does not start until E14.5 and older mice have less severe cystic dysplasia than Fgfr1/2(NP-/-) To determine the role of Frs2α alone in nephron progenitors, we generated Six2creFrs2'A(flox/flox) (Frs2a(NP-/-)) mice. Frs2a(NP-/-)mice also develop nephron progenitor depletion and renal cysts, although these occurred later and were less severe than in the other Six2cre mutant mice. The nephron progenitor loss in all Six2cre mutant lines was associated with decreased Cited1 expression and increased apoptosis versus controls. FAC-sorted nephron progenitors in Six2cre Frs2'A(flox/flox) mice demonstrated evidence of increased Notch activity versus controls, which likely drives the progenitor defects. Thus, Fgfr1 and Fgfr2 have synergistic roles in maintaining nephron progenitors; furthermore, Fgfr signaling in nephron progenitors appears to be mediated predominantly by Frs2α.
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Valeria
authors: V
authors: Di Giovanni
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Kenneth A
authors: KA
authors: Walker
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Daniel
authors: D
authors: Bushnell
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Caitlin
authors: C
authors: Schaefer
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Sunder
authors: S
authors: Sims-Lucas
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors: Pawan
authors: P
authors: Puri
authors: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA; Rangos Research Center, Children׳s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. Electronic address: batescm@upmc.edu.
authors: Carlton M
authors: CM
authors: Bates
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009399:Nephrons / Q000196:embryology*; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C102208:Cited1 protein, mouse; C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D015534:Trans-Activators
keywords: Fibroblast growth factor receptors; Frs2α; Kidney development; Nephron progenitors
references: Cell. 1999 Nov 12;99(4):377-86
references: 10571180
references: Mol Cell Biol. 2005 May;25(10):4105-16
references: 15870281
references: Development. 2005 Sep;132(17):3859-71
references: 16049111
references: Development. 2005 Sep;132(17):3847-57
references: 16049112
references: Dev Biol. 2006 Mar 15;291(2):325-39
references: 16442091
references: Microsc Res Tech. 2006 Dec;69(12):1014-20
references: 17013912
references: Dev Biol. 2009 Sep 15;333(2):312-23
references: 19591821
references: Development. 2009 Nov;136(21):3557-66
references: 19793891
references: Dev Biol. 2009 Nov 1;335(1):106-19
references: 19715689
references: Am J Physiol Renal Physiol. 2009 Nov;297(5):F1208-19
references: 19741018
references: J Am Soc Nephrol. 2009 Dec;20(12):2525-33
references: 19833900
references: J Urol. 2010 May;183(5):2077-84
references: 20303521
references: J Am Soc Nephrol. 2010 May;21(5):803-10
references: 20299358
references: Dev Dyn. 2011 Jan;240(1):240-9
references: 21128305
references: Development. 2011 Apr;138(7):1275-80
references: 21350013
references: Development. 2011 Apr;138(7):1247-57
references: 21350016
references: Development. 2011 Jul;138(13):2717-27
references: 21613322
references: Development. 2011 Dec;138(23):5099-112
references: 22031548
references: J Am Soc Nephrol. 2012 Apr;23(4):607-17
references: 22282599
references: Cold Spring Harb Perspect Biol. 2012 May;4(5). pii: a008300. doi: 10.1101/cshperspect.a008300
references: 22550230
references: Dev Cell. 2012 Jun 12;22(6):1191-207
references: 22698282
references: PLoS One. 2012;7(9):e44869
references: 22984579
references: PLoS One. 2013;8(2):e56062
references: 23409123
references: Development. 1999 Dec;126(24):5847-56
references: 10572058
references: Mol Cell Biol. 2000 Feb;20(3):979-89
references: 10629055
references: Mol Cell Biol. 2000 Mar;20(6):2260-8
references: 10688672
references: Genesis. 2000 Feb;26(2):162-4
references: 10686619
references: Endocr Relat Cancer. 2000 Sep;7(3):165-97
references: 11021964
references: Development. 2001 Apr;128(7):1045-57
references: 11245570
references: Oncogene. 2001 Sep 10;20(40):5623-37
references: 11607814
references: Dev Cell. 2002 Jan;2(1):103-13
references: 11782318
references: Genes Dev. 2002 Jun 15;16(12):1446-65
references: 12080084
references: Development. 2003 Mar;130(6):1101-11
references: 12571102
references: J Biol Chem. 2003 May 2;278(18):16405-13
references: 12598523
references: Nature. 1994 Jan 27;367(6461):380-3
references: 8114940
references: Genes Dev. 1994 Dec 15;8(24):3032-44
references: 8001822
references: Genes Dev. 1994 Dec 15;8(24):3045-57
references: 8001823
references: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4696-700
references: 7753867
references: Nat Genet. 1996 Apr;12(4):390-7
references: 8630492
references: Am J Physiol. 1997 Nov;273(5 Pt 2):F757-67
references: 9374839
references: Nat Med. 1998 Feb;4(2):201-7
references: 9461194
references: Development. 1998 Feb;125(4):753-65
references: 9435295
references: EMBO J. 1998 Mar 16;17(6):1642-55
references: 9501086
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5082-7
references: 9560232
references: Development. 1998 Sep;125(18):3615-23
references: 9716527
references: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18603-8
references: 17132737
references: Development. 2007 Feb;134(4):801-11
references: 17229764
references: Genesis. 2007 Sep;45(9):554-9
references: 17868091
references: Dev Biol. 2008 Jan 1;313(1):234-45
references: 18061157
references: Cell Stem Cell. 2008 Aug 7;3(2):169-81
references: 18682239
references: Pediatr Res. 2008 Dec;64(6):592-8
references: 18670373
references: Dev Biol. 2004 Dec 15;276(2):403-15
references: 15581874