title: Yap and Taz are required for Ret-dependent urinary tract morphogenesis.
abstract: Despite the high occurrence of congenital abnormalities of the lower urinary tract in humans, the molecular, cellular and morphological aspects of their development are still poorly understood. Here, we use a conditional knockout approach to inactivate within the nephric duct (ND) lineage the two effectors of the Hippo pathway, Yap and Taz. Deletion of Yap leads to hydronephrotic kidneys with blind-ending megaureters at birth. In Yap mutants, the ND successfully migrates towards, and contacts, the cloaca. However, close analysis reveals that the tip of the Yap(-/-) ND forms an aberrant connection with the cloaca and does not properly insert into the cloaca, leading to later detachment of the ND from the cloaca. Taz deletion from the ND does not cause any defect, but analysis of Yap(-/-);Taz(-/-) NDs indicates that both genes play partially redundant roles in ureterovesical junction formation. Aspects of the Yap(-/-) phenotype resemble hypersensitivity to RET signaling, including excess budding of the ND, increased phospho-ERK and increased expression of Crlf1, Sprouty1, Etv4 and Etv5. Importantly, the Yap(ND) (-/-) ND phenotype can be largely rescued by reducing Ret gene dosage. Taken together, these results suggest that disrupting Yap/Taz activities enhances Ret pathway activity and contributes to pathogenesis of lower urinary tract defects in human infants.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5 reginensi@lunenfeld.ca mcneill@lunenfeld.ca.
authors.forename: Antoine
authors.initials: A
authors.lastname: Reginensi
authors.affiliation: Departments of Internal Medicine (Renal Division) and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.affiliation: Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Canada H3A 1A3.
authors.forename: Sami Kamel
authors.initials: SK
authors.lastname: Boualia
authors.affiliation: Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Canada H3A 1A3.
authors.forename: Maxime
authors.initials: M
authors.lastname: Bouchard
authors.affiliation: Departments of Internal Medicine (Renal Division) and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5 Department of Molecular Genetics, University of Toronto, Toronto, Canada M5G 1X5 reginensi@lunenfeld.ca mcneill@lunenfeld.ca.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins; D005455:Fluorescent Antibody Technique; D005697:Galactosides; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007211:Indoles; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014551:Urinary Tract / Q000196:embryology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D005697:Galactosides; D007211:Indoles; D010750:Phosphoproteins; D015534:Trans-Activators; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D001973:Bromodeoxyuridine; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: CAKUT; Lower urinary tract; Nephric duct; Ret; Taz; Yap