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

• 成果类型: Article
• 署名作者: Gregoire, Elodie P.; De Cian, Marie-Cecile; Migale, Roberta; Perea-Gomez, Aitana; Schaub, Sebastien; Bellido-Carreras, Natividad; Stevant, Isabelle; Mayere, Chloe; Neirijnck, Yasmine; Loubat, Agnes; Rivaud, Paul; Sopena, Miriam Llorian; Lachambre, Simon; Linssen, Margot M.; Hohenstein, Peter; Lovell-Badge, Robin; Nef, Serge; Chalmel, Frederic; Schedl, Andreas; Chaboissier, Marie-Christine
• 署名单位: Universite Cote d'Azur; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Francis Crick Institute; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); University of Geneva; University of Geneva; Ecole des Hautes Etudes en Sante Publique (EHESP); Universite de Rennes; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12287
• DOI: 10.1126/science.add8831
• 发表日期: 2023-11-03
• 关键词: cell lineage specification; gonadal sex determination; subnuclear localization; sertoli-cells; sry; differentiation; transcription; expression; sox9; granulosa

摘要

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.