title: Fgfr2 is integral for bladder mesenchyme patterning and function.
abstract: While urothelial signals, including sonic hedgehog (Shh), drive bladder mesenchyme differentiation, it is unclear which pathways within the mesenchyme are critical for its development. Studies have shown that fibroblast growth factor receptor 2 (Fgfr2) is necessary for kidney and ureter mesenchymal development. Our objective was to determine the role of Fgfr2 in bladder mesenchyme. We usedTbx18cremice to deleteFgfr2in bladder mesenchyme (Fgfr2BM-/-). We performed three-dimensional reconstructions, quantitative real-time PCR, in situ hybridization, immunolabeling, ELISAs, immunoblotting, void stain on paper, ex vivo bladder sheet assays, and in vivo decerebrated cystometry. Compared with controls, embryonic (E)day 16.5(E16.5)Fgfr2BM-/-bladders have thin muscle layers with reduced α-smooth muscle actin levels and thickened lamina propria with increased collagen expression that intrudes into muscle. From postnatal (P)day 1(P1) toP30,Fgfr2BM-/-bladders demonstrate progressive muscle loss and increased collagen expression. PostnatalFgfr2BM-/-bladder sheets exhibit decreased contractility and increased passive stretch tension compared with controls. In vivo cystometry revealed high baseline and threshold pressures and shortened intercontractile intervals inFgfr2BM-/-bladders compared with controls. Mechanistically, while Shh expression appears normal, mRNA and protein readouts of hedgehog activity are increased inE16.5 Fgfr2BM-/-bladders compared with controls. Moreover,E16.5Fgfr2BM-/-bladders exhibit higher levels ofCdoandBoc, hedgehog coreceptors that enhance sensitivity to Shh, than controls.Fgfr2is critical for bladder mesenchyme patterning by virtue of its role in modulation of hedgehog signaling.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: I
authors.initials: I
authors.lastname: Zabbarova
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: C M
authors.initials: CM
authors.lastname: Schaefer
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: D
authors.initials: D
authors.lastname: Bushnell
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: W C
authors.initials: WC
authors.lastname: De Groat
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: A
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; batescm@upmc.edu.|Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: C M
authors.initials: CM
authors.lastname: Bates
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000378:metabolism*; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle; D010641:Phenotype; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D001743:Urinary Bladder / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D014563:Urodynamics
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; C510745:Boc protein, mouse; C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D003094:Collagen; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: bladder development; bladder dysfunction; fibroblast growth factor receptor 2