title: Betacellulin transgenic mice develop urothelial hyperplasia and show sex-dependent reduction in urinary major urinary protein content.
abstract: The epidermal growth factor (EGF)-like ligands and their cognate ERBB1-4 receptors represent important signaling pathways that regulate tissue and cell proliferation, differentiation and regeneration in a wide variety of tissues, including the urogenital tract. Betacellulin (BTC) can activate all four ERBB tyrosine kinase receptors and is a multifunctional EGF-like ligand with diverse roles in β cell differentiation, bone maturation, formation of functional epithelial linings and vascular permeability in different organs. Using transgenic BTC mice, we have studied the effect of constitutive systemic BTC over-expression on the urinary bladder. BTC was detected in microvascular structures of the stromal bladder compartment and in umbrella cells representing the protective apical lining of the uroepithelium. ERBB1 and ERBB4 receptors were co-localized in the urothelium. Mice transgenic for BTC and double transgenic for both BTC and the dominant kinase-dead mutant of EGFR (Waved 5) developed hyperplasia of the uroepithelium at 5months of age, suggesting that urothelial hyperplasia was not exclusively dependent on ERBB1/EGFR. Mass spectrometric analysis of urine revealed a significant down-regulation of major urinary proteins in female BTC transgenic mice, suggesting a novel role for systemic BTC in odor-based signaling in female transgenic BTC mice.
authors.affiliation: Dept. of Human Anatomy and Cell Science, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada; National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
authors.forename: Helene
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.affiliation: Dept. of Human Anatomy and Cell Science, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Glogowska
authors.affiliation: Dept. of Human Anatomy and Cell Science, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Arnold
authors.affiliation: Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Dept. of Human Anatomy and Cell Science, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada; Dept. of Medical Microbiology & Infectious Diseases, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada; Dept. of Surgery, University of Manitoba, Faculty of Health Sciences, College of Medicine, Winnipeg, MB R3E 0J9, Canada. Electronic address: thomas.klonisch@umanitoba.ca.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
mesh_terms: D000818:Animals; D066259:Betacellulin / Q000235:genetics* / Q000378:metabolism; D002853:Chromatography, Liquid; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006965:Hyperplasia; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D053719:Tandem Mass Spectrometry; D015854:Up-Regulation; D019459:Urothelium / Q000473:pathology*
chemical_list: D066259:Betacellulin; D008024:Ligands; D011506:Proteins; C035737:major urinary proteins; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
keywords: BTC; Betacellulin; Bladder; EGF receptor; ERBB1; ERBB4; MUP; Major urinary protein; Uroepithelium