Loss of peri-Wolffian duct stromal Frs2? expression in mice leads to abnormal ureteric bud induction and vesicoureteral reflux.

ABSTRACT: BackgroundFibroblast growth factor receptor 2 (Fgfr2) deletion from murine peri-Wolffian duct stroma (ST) results in aberrant ureteric bud induction, abnormal ureteral insertion into the bladder, and high rates of vesicoureteral reflux (VUR). It is unclear which receptor docking protein(s) is/are responsible for Fgfr2 actions in these tissues. We investigated whether the docking protein, fibroblast receptor substrate 2? (Frs2?), had a role in peri-Wolffian duct ST similar to Fgfr2.MethodsWe conditionally deleted Frs2? in peri-Wolffian duct ST with a Tbx18cre mouse line (Frs2?ST-/-). We assessed for ureteric induction defects and alterations in downstream targets mediating defects. We performed euthanized cystograms and assessed ureter-bladder junctions by three-dimensional (3D) reconstructions.ResultsEmbryonic day (E) 11.5 Frs2?ST-/- embryos had many displaced ureteric bud induction sites when compared with controls. E11.0 Frs2?ST-/- embryos had decreased Bmp4 expression and signaling, which can cause abnormal ureteric bud induction. Postnatal day 1 (P1) and P30 Frs2?ST-/- mice had higher VUR rates and grades vs. CONTROLS:Mutant refluxing ureters that inserted improperly into the bladder had shortened intravesicular tunnels (IVTs) when compared with controlsConclusionFrs2?ST-/- embryos have aberrant ureteric induction sites, improper ureteral insertion, shortened intravesicular lengths, and VUR. Induction site defects appear secondary to reduced Bmp4 expression, similar to Fgfr2 mutants.

SUBMITTER: Narla D 

PROVIDER: S-EPMC5701656 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature