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 (Fgfr)2 is necessary for kidney and ureter mesenchymal development. The objective of the present study was to determine the role of Fgfr2 in the bladder mesenchyme. We used Tbx18cre mice to delete Fgfr2 in the bladder mesenchyme (Fgfr2(BM-/-)). We performed three-dimensional reconstructions, quantitative real-time PCR, in situ hybridization, immunolabeling, ELISAs, immunoblot analysis, void stain on paper, ex vivo bladder sheet assays, and in vivo decerebrated cystometry. Compared with control bladders, embryonic day 16.5 (E16.5) Fgfr2(BM-/-) bladders had thin muscle layers with less α-smooth muscle actin and thickened lamina propria with increased collagen type Ia and IIIa that intruded into the muscle. The reciprocal changes in mutant layer thicknesses appeared partly due to a cell fate switch. From postnatal days 1 to 30, Fgfr2(BM-/-) bladders demonstrated progressive muscle loss and increased collagen expression. Postnatal Fgfr2(BM-/-) bladder sheets exhibited decreased agonist-mediated contractility and increased passive stretch tension versus control bladder sheets. Cystometry revealed high baseline and threshold pressures and shortened intercontractile intervals in Fgfr2(BM-/-) versus control bladders. Mechanistically, whereas Shh expression appeared normal, mRNA and protein readouts of hedgehog activity were increased in E16.5 Fgfr2(BM-/-) versus control bladders. Moreover, E16.5 Fgfr2(BM-/-) bladders exhibited higher levels of Cdo and Boc, hedgehog coreceptors that enhance sensitivity to Shh, compared with control bladders. In conclusion, loss of Fgfr2 in the bladder mesenchyme leads to abnormal bladder morphology and decreased compliance and contractility.
authors: Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
authors: K A
authors: KA
authors: Walker
authors: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors: Y
authors: Y
authors: Ikeda
authors: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors: I
authors: I
authors: Zabbarova
authors: Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
authors: C M
authors: CM
authors: Schaefer
authors: Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
authors: D
authors: D
authors: Bushnell
authors: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors: W C
authors: WC
authors: De Groat
authors: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors: A
authors: A
authors: Kanai
authors: Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Division of Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania batescm@upmc.edu.
authors: C M
authors: CM
authors: Bates
mesh_terms: D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003187:Compliance; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D053823:Hedgehog Proteins / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000002:abnormalities / Q000378:metabolism*; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D009929:Organ Size; D010641:Phenotype; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D001743:Urinary Bladder / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D014563:Urodynamics
chemical_list: 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; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: bladder development; bladder dysfunction; fibroblast growth factor receptor 2
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