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

Elodie P. Gregoire; Marie Cécile De Cian; Roberta Migale; Aitana Perea-Gomez; Sébastien Schaub; Natividad Bellido-Carreras; Isabelle Stévant; Chloé Mayère; Yasmine Neirijnck; Agnès Loubat; Paul Rivaud; Miriam Llorian Sopena; Simon Lachambre; Margot M. Linssen; Peter Hohenstein; Robin Lovell-Badge; Serge Nef; Frédéric Chalmel; Andreas Schedl; Marie Christine Chaboissier

doi:10.1126/science.add8831

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

Elodie P. Gregoire, Marie Cécile De Cian, Roberta Migale, Aitana Perea-Gomez, Sébastien Schaub, Natividad Bellido-Carreras, Isabelle Stévant, Chloé Mayère, Yasmine Neirijnck, Agnès Loubat, Paul Rivaud, Miriam Llorian Sopena, Simon Lachambre, Margot M. Linssen, Peter Hohenstein, Robin Lovell-Badge, Serge Nef, Frédéric Chalmel, Andreas Schedl, Marie Christine Chaboissier

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9 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	600-605
Number of pages	6
Journal	Science
Volume	382
Issue number	6670
DOIs	https://doi.org/10.1126/science.add8831
State	Published - 3 Nov 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.

Funding

This research was supported by Agence Nationale de la Recherche grant ANR-19-CE14-0022 SexDiff (M.-C.C.), Fondation Maladies Rares grant FONDATION-GenOmics 2018-1 181003 RNAseq (M.-C.C.), Agence Nationale de la Recherche grant ANR-20-CE14-0022 Ardigerm (M.-C.C.), and Swiss National Science Foundation grants 31003A_173070 (S.N.) and 310030_200316 (S.N.). The Francis Crick Institute receives its core funding from Cancer Research UK (FC001107), the UK Medical Research Council (FC001107), Wellcome (FC001107), and the UK Medical Research Council (U117512772) (R.M., M.L.S., and R.L.-B.).

Funders	Funder number
Wellcome Trust	U117512772
Fondation Maladies Rares	FONDATION-GenOmics 2018-1 181003, ANR-20-CE14-0022
Medical Research Council
Cancer Research UK	FC001107
Agence Nationale de la Recherche	ANR-19-CE14-0022
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310030_200316, 31003A_173070

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Gregoire, E. P., De Cian, M. C., Migale, R., Perea-Gomez, A., Schaub, S., Bellido-Carreras, N., Stévant, I., Mayère, C., Neirijnck, Y., Loubat, A., Rivaud, P., Sopena, M. L., Lachambre, S., Linssen, M. M., Hohenstein, P., Lovell-Badge, R., Nef, S., Chalmel, F., Schedl, A., & Chaboissier, M. C. (2023). The −KTS splice variant of WT1 is essential for ovarian determination in mice. Science, 382(6670), 600-605. https://doi.org/10.1126/science.add8831

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title = "The −KTS splice variant of WT1 is essential for ovarian determination in mice",

abstract = "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.",

author = "Gregoire, {Elodie P.} and {De Cian}, {Marie C{\'e}cile} and Roberta Migale and Aitana Perea-Gomez and S{\'e}bastien Schaub and Natividad Bellido-Carreras and Isabelle St{\'e}vant and Chlo{\'e} May{\`e}re and Yasmine Neirijnck and Agn{\`e}s Loubat and Paul Rivaud and Sopena, {Miriam Llorian} and Simon Lachambre and Linssen, {Margot M.} and Peter Hohenstein and Robin Lovell-Badge and Serge Nef and Fr{\'e}d{\'e}ric Chalmel and Andreas Schedl and Chaboissier, {Marie Christine}",

year = "2023",

month = nov,

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doi = "10.1126/science.add8831",

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Gregoire, EP, De Cian, MC, Migale, R, Perea-Gomez, A, Schaub, S, Bellido-Carreras, N, Stévant, I, Mayère, C, Neirijnck, Y, Loubat, A, Rivaud, P, Sopena, ML, Lachambre, S, Linssen, MM, Hohenstein, P, Lovell-Badge, R, Nef, S, Chalmel, F, Schedl, A & Chaboissier, MC 2023, 'The −KTS splice variant of WT1 is essential for ovarian determination in mice', Science, vol. 382, no. 6670, pp. 600-605. https://doi.org/10.1126/science.add8831

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AU - Gregoire, Elodie P.

AU - De Cian, Marie Cécile

AU - Migale, Roberta

AU - Perea-Gomez, Aitana

AU - Schaub, Sébastien

AU - Bellido-Carreras, Natividad

AU - Stévant, Isabelle

AU - Mayère, Chloé

AU - Neirijnck, Yasmine

AU - Loubat, Agnès

AU - Rivaud, Paul

AU - Sopena, Miriam Llorian

AU - Lachambre, Simon

AU - Linssen, Margot M.

AU - Hohenstein, Peter

AU - Lovell-Badge, Robin

AU - Nef, Serge

AU - Chalmel, Frédéric

AU - Schedl, Andreas

AU - Chaboissier, Marie Christine

PY - 2023/11/3

Y1 - 2023/11/3

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

Abstract

Bibliographical note

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