ESPEYB21 6. Differences of Sexual Development (DSD) and Gender Incongruence (GI) DSD - Novel Genes and Mechanisms involved in Gonadal Development (4 abstracts)
6.1. The -KTS splice variant of WT1 is essential for ovarian determination in mice
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
Science. 2023 Nov 3;382(6670):600-606. doi: 10.1126/science.add8831. PMID: 37917714
Brief Summary: This study examined the complex process of sex determination in mice, with a specific focus on the role of WT1 isoforms, +KTS and -KTS, during gonadal development. The study provides insights into how the balance between these isoforms impacts sexual differentiation, with broader implications for understanding gonadal dysgenesis conditions, like Frasier syndrome.
While the role of the SRY gene in testicular determination is well understood, the factors influencing ovarian determination are less clear. This study highlights the crucial role of the -KTS isoform in female development and suggests that sex determination depends not only on the presence of key factors like Sry for males and -KTS for females but also on the precise timing of their expression.
A key player in early gonadal development is the Wilms’ tumor suppressor (WT1), a zinc finger transcriptional regulator located on chromosome 11p13. WT1 produces two major isoforms through alternative splicing: +KTS, which includes three amino acids (KTS) between the last two zinc fingers, and -KTS, which excludes them. Mutations in the donor splice site in intron 9 of WT1, which cause Frasier syndrome, lead to an imbalance favoring the -KTS isoform over +KTS, resulting in 46,XY gonadal dysgenesis.
This study examined the gonads of -KTS and +KTS knockout mouse models using transcriptomic analyses. They found that the absence of +KTS is compensated by an increase in -KTS expression, and that this increase of -KTS rather than the loss of +KTS, is involved in the pathogenesis of gonadal dysgenesis in Frasier syndrome. Their results indicate that elevated -KTS expression prevents Sry upregulation, promotes pre-granulosa cell differentiation, and triggers premature ovarian differentiation, disrupting testicular development in XY mice. The study also underscores the essential role of the -KTS isoform in initiating ovarian development in XX embryos and maintaining Sertoli cell differentiation in XY embryos after Sry expression.
Although direct comparisons between mouse and human data are challenging due to differences in the timing and dynamics of sex determination, the findings suggest that the -KTS isoform of WT1 is crucial for gonadal development and is essential for initiating ovarian differentiation.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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