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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.

SUBMITTER: Gregoire EP

PROVIDER: S-EPMC7615308 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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

Gregoire Elodie P EP De Cian Marie-Cécile MC Migale Roberta R Perea-Gomez Aitana A Schaub Sébastien S Bellido-Carreras Natividad N Stévant Isabelle I Mayère Chloé C Neirijnck Yasmine Y Loubat Agnès A Rivaud Paul P Sopena Miriam Llorian ML Lachambre Simon S Linssen Margot M MM Hohenstein Peter P Lovell-Badge Robin R Nef Serge S Chalmel Frédéric F Schedl Andreas A Chaboissier Marie-Christine MC

Science (New York, N.Y.) 20231102 6670

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 vari ...[more]

PMID: 37917714

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Project description:Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer.

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

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The <i>-KTS</i> splice variant of WT1 is essential for ovarian determination in mice.

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

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The &lt;i&gt;-KTS&lt;/i&gt; splice variant of WT1 is essential for ovarian determination in mice.

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OmicsDI is part of the ELIXIR infrastructure

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The <i>-KTS</i> splice variant of WT1 is essential for ovarian determination in mice.