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dc.contributor.authorVaquero, Marta
dc.contributor.authorCuesta, Sara
dc.contributor.authorAnerillas, Carlos
dc.contributor.authorAltés, Gisela
dc.contributor.authorRibera i Calvet, Joan
dc.contributor.authorBasson, M. Albert
dc.contributor.authorLicht, Jonathan D.
dc.contributor.authorEgea Navarro, Joaquim
dc.contributor.authorEncinas Martín, Mario
dc.date.accessioned2019-12-09T12:07:37Z
dc.date.available2019-12-09T12:07:37Z
dc.date.issued2019-08-01
dc.identifier.issn1046-6673
dc.identifier.urihttp://hdl.handle.net/10459.1/67681
dc.description.abstractBackground: Congenital anomalies of the kidney and urinary tract (CAKUT) is a group of diseases that include a broad spectrum of developmental defects of the genitourinary system. Mouse models indicate that perturbations of the GDNF-Ret signaling pathway are a major genetic cause of CAKUT. Sprouty1 is an intracellular Ret inhibitor whose mutation results in supernumerary kidneys, megaureters, and hydronephrosis in mice. Both the molecular mechanisms and the structural domains critical for Sprouty function are a matter of controversy, partly because studies pursuing this objective rely on ectopic overexpression in cell lines. A conserved N-terminal tyrosine has been frequently, but not always, identified as critical for their function in vitro. Methods: We have generated Sprouty1 knockin mice bearing a tyrosine-to-alanine substitution in position 53, corresponding to the conserved N-terminal tyrosine of Sprouty1. We have characterized development of the genitourinary systems of these mice via different methods, including the use of reporter mice expressing EGFP form the Ret locus, and whole mount cytokeratin staining. Results: Mice lacking this tyrosine grow ectopic ureteric buds that ultimately will form supernumerary kidneys, a phenotype indistinguishable to that of Sprouty1 knockout mice. Sprouty1 knockin mice also present megaureters and vesicoureteral reflux, caused by failure of ureters to separate from Wolffian ducts and migrate to their definitive position. Conclusions: Tyrosine 53 is absolutely necessary to convey Sprouty1 function during genitourinary development.
dc.description.sponsorshipThis work was supported by grants BFU2010-47175-P and BFU2017-83646-P (AEI/FEDER, UE) from MINECO to ME. MV was supported by a predoctoral fellowship from AGAUR. CA was supported by a predoctoral fellowship from Universitat de Lleida. SC was supported by a Cofund action from the Marie Curie program of the EU. We are grateful to Dr. Sanjay Jain (Washington University, St Louis) for sharing RetEGFP mice, and to Dr. Tung-Tien Sun (New York University) for Uroplakin antibody. We thank Anna Macià (IRB Lleida) for her contribution to the initial development of this manuscript, as well as Marta Hereu, Maria Santacana, Mónica Domingo and Maria Carrele for their excellent technical assistance.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherAmerican Society of Nephrology
dc.relationMICINN/PN2008-2011/BFU2010-47175-P
dc.relationMINECO/PN2017-2020/BFU2017-83646-P
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1681/ASN.2018111085
dc.relation.ispartofJournal of the American Society of Nephrology, 2019, vol. 30, núm. 8, p. 1398-1411
dc.subjectSprouty
dc.subjectRet
dc.subjectGenitourinary Development
dc.subjectWolffian Duct
dc.subjectUreteric bud
dc.titleSprouty1 controls genitourinary development via its N-terminal tyrosine
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2019-12-09T12:07:38Z
dc.identifier.idgrec028598
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1681/ASN.2018111085


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