title: Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux.
abstract: OBJECTIVE
  Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity.
  
  
  METHODS
  We conditionally deleted Fgfr2 in ST (Fgfr2(ST-/-)) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects.
  
  
  RESULTS
  We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2(ST-/-) mice at embryonic day (E) 10.5. E11.5 Fgfr2(ST-/-) mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2(ST-/-) mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2(ST-/-) mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes.
  
  
  CONCLUSIONS
  Mutations in FGFR2 could possibly cause VUR in humans.
authors: Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors: Kenneth A
authors: KA
authors: Walker
authors: Sunder
authors: S
authors: Sims-Lucas
authors: Valeria E
authors: VE
authors: Di Giovanni
authors: Caitlin
authors: C
authors: Schaefer
authors: Whitney M
authors: WM
authors: Sunseri
authors: Tatiana
authors: T
authors: Novitskaya
authors: Mark P
authors: MP
authors: de Caestecker
authors: Feng
authors: F
authors: Chen
authors: Carlton M
authors: CM
authors: Bates
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014513:Ureter / Q000002:abnormalities* / Q000196:embryology*; D001743:Urinary Bladder / Q000002:abnormalities / Q000196:embryology; D014564:Urogenital Abnormalities / Q000196:embryology / Q000235:genetics; D014718:Vesico-Ureteral Reflux / Q000235:genetics*; D014928:Wolffian Ducts / Q000378:metabolism*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D020825:T-Box Domain Proteins; C420983:Tbx18 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2