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Sprouty1 controls genitourinary development via its N-terminal tyrosine

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Issue date
2019-08-01
Author
Vaquero, Marta
Cuesta, Sara
Anerillas, Carlos
Altés, Gisela
Ribera i Calvet, Joan
Basson, M. Albert
Licht, Jonathan D.
Egea Navarro, Joaquim
Encinas Martín, Mario
Suggested citation
Vaquero, Marta; Cuesta, Sara; Anerillas, Carlos; Altés, Gisela; Ribera i Calvet, Joan; Basson, M. Albert; ... Encinas Martín, Mario. (2019) . Sprouty1 controls genitourinary development via its N-terminal tyrosine. Journal of the American Society of Nephrology, 2019, vol. 30, núm. 8, p. 1398-1411. https://doi.org/10.1681/ASN.2018111085.
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Abstract
Background: 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.
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http://hdl.handle.net/10459.1/67681
DOI
https://doi.org/10.1681/ASN.2018111085
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Journal of the American Society of Nephrology, 2019, vol. 30, núm. 8, p. 1398-1411
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