The -KTS splice variant of WT1 is essential for ovarian determination in mice.

Autor: Gregoire EP; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., De Cian MC; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Migale R; The Francis Crick Institute, London NW1 1AT, UK., Perea-Gomez A; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Schaub S; Sorbonne Université, CNRS, Development Biology Laboratory (LBDV), 06234 Villefranche sur Mer, France., Bellido-Carreras N; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Stévant I; Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland.; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland., Mayère C; Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland.; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland., Neirijnck Y; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Loubat A; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Rivaud P; Univ Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000 Rennes, France., Sopena ML; The Francis Crick Institute, London NW1 1AT, UK., Lachambre S; Infinity, INSERM, CNRS, University Toulouse III, 31024 Toulouse, France., Linssen MM; Central Animal and Transgenic Facility and Department of Human Genetics, Leiden University Medical Center, 2333ZA Leiden, Netherlands., Hohenstein P; Central Animal and Transgenic Facility and Department of Human Genetics, Leiden University Medical Center, 2333ZA Leiden, Netherlands., Lovell-Badge R; The Francis Crick Institute, London NW1 1AT, UK., Nef S; Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland.; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland., Chalmel F; Univ Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000 Rennes, France., Schedl A; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France., Chaboissier MC; Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Nov 03; Vol. 382 (6670), pp. 600-606. Date of Electronic Publication: 2023 Nov 02.
DOI: 10.1126/science.add8831
Abstrakt: Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene Sry has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - KTS variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized Sry expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.
Databáze: MEDLINE
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