title: Role of Wnt5a-Ror2 signaling in morphogenesis of the metanephric mesenchyme during ureteric budding.
abstract: Development of the metanephric kidney begins with the induction of a single ureteric bud (UB) on the caudal Wolffian duct (WD) in response to GDNF (glial cell line-derived neurotrophic factor) produced by the adjacent metanephric mesenchyme (MM). Mutual interaction between the UB and MM maintains expression of GDNF in the MM, thereby supporting further outgrowth and branching morphogenesis of the UB, while the MM also grows and aggregates around the branched tips of the UB. Ror2, a member of the Ror family of receptor tyrosine kinases, has been shown to act as a receptor for Wnt5a to mediate noncanonical Wnt signaling. We show that Ror2 is predominantly expressed in the MM during UB induction and that Ror2- and Wnt5a-deficient mice exhibit duplicated ureters and kidneys due to ectopic UB induction. During initial UB formation, these mutant embryos show dysregulated positioning of the MM, resulting in spatiotemporally aberrant interaction between the MM and WD, which provides the WD with inappropriate GDNF signaling. Furthermore, the numbers of proliferating cells in the mutant MM are markedly reduced compared to the wild-type MM. These results indicate an important role of Wnt5a-Ror2 signaling in morphogenesis of the MM to ensure proper epithelial tubular formation of the UB required for kidney development.
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan nishita@med.kobe-u.ac.jp minami@kobe-u.ac.jp.
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Qiao
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okinaka
authors.affiliation: Department of Developmental Biology, Faculty of Medicine, Shimane University, Izumo, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Clinical Nursing, Faculty of Medicine, Shimane University, Izumo, Japan.
authors.forename: Ryuju
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Developmental Biology, Faculty of Medicine, Shimane University, Izumo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Otani
authors.affiliation: Department of Bone and Skeletal Research, Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Münster, Münster, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan nishita@med.kobe-u.ac.jp minami@kobe-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D007668:Kidney / Q000196:embryology*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009024:Morphogenesis; D009924:Organ Culture Techniques; D038081:Organogenesis; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D014513:Ureter / Q000196:embryology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D014928:Wolffian Ducts / Q000196:embryology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse