title: UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice.
abstract: During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in Gata2 hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the Gata2 hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2-BMP4 epistatic relationship by demonstrating that reporter gene expression from a Bmp4 bacterial artificial chromosome (BAC) transgene is altered in Gata2 hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ainoya
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Shin'ya
authors.initials: S
authors.lastname: Ohmori
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.forename: Masanobu
authors.initials: M
authors.lastname: Morita
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Chandler
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Mortlock
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D014564:Urogenital Abnormalities; D014566:Urogenital System / Q000196:embryology / Q000378:metabolism; D014718:Vesico-Ureteral Reflux / Q000209:etiology / Q000235:genetics
chemical_list: D055415:Bone Morphogenetic Protein 4; D050989:GATA2 Transcription Factor