title: Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension.
abstract: Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations.
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Kangsun
authors.initials: K
authors.lastname: Yun
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Rieko
authors.initials: R
authors.lastname: Ajima
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Costantini
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA and perantoa@mail.nih.gov.
authors.forename: Alan O
authors.initials: AO
authors.lastname: Perantoni
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics*; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D014513:Ureter / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics*; D000071818:Wnt-5a Protein; D014928:Wolffian Ducts / Q000254:growth & development / Q000378:metabolism / Q000473:pathology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse; C045073:Cre recombinase; D019426:Integrases
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