Science. 2023 Nov 3;382(6670):600-606. doi: 10.1126/science.add8831
The −KTS splice variant of WT1 is essential for ovarian determination in mice
Elodie P. Gregoire1, Marie-Cécile De Cian1, Roberta Migale2, Aitana Perea-Gomez1, Sébastien Schaub3, Natividad Bellido-Carreras1, Isabelle Stévant4,5, Chloé Mayère4,5, Yasmine Neirijnck1, Agnès Loubat1, Paul Rivaud6, Miriam Llorian Sopena2, Simon Lachambre7, Margot M. Linssen8, Peter Hohenstein8, Robin Lovell-Badge2, Serge Nef4,5, Frédéric Chalmel6, Andreas Schedl1, Marie-Christine Chaboissier1
1Université Côte d’Azur, INSERM, CNRS, Institut de Biologie Valrose (iBV), 06108 Nice, France.
2The Francis Crick Institute, London NW1 1AT, UK.
3Sorbonne Université, CNRS, Development Biology Laboratory (LBDV), 06234 Villefranche sur Mer, France.
4Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland.
5iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland.
6Univ Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000 Rennes, France.
7Infinity, INSERM, CNRS, University Toulouse III, 31024 Toulouse, France.
8Central Animal and Transgenic Facility and Dept. Human Genetics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
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.