ArticlePLoS genetics2019
CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 75 citations in OpenAlex.
- Strain-Dependent Functional Variation of a Sex Specific Sox9 Enhancer.Genes to cells : devoted to molecular & cellular mechanisms · 2026Article
- Exploring the underlying gene expression profiles of differences of sex development phenotypes through transcriptome analysis.Scientific reports · 2026Article
- Single-nucleus multiomics of murine gonads reveals transcriptional regulatory network underlying supporting lineage differentiation.Science advances · 2026Article
- Chromatin-Based Control of Mammalian Sex Determination: Integrating Epigenetic and Metabolic Mechanisms.Advances in experimental medicine and biology · 2026Review
- KDM6B is a conserved activator at the top of the male sex determination pathway.Development (Cambridge, England) · 2025Article
- Overexpression ofZoological research · 2024Article
- A candidate sex determination locus in amphibians which evolved by structural variation between X- and Y-chromosomes.Nature communications · 2024Article
- Inefficient Sox9 upregulation and absence of Rspo1 repression lead to sex reversal in the B6.XYTIR mouse gonad†.Biology of reproduction · 2024Article
- Whole-Genome Identification and Characterization of the DKK Gene Family and Its Transcription Profiles: An Analysis of the Chinese Soft-Shell Turtle (Animals : an open access journal from MDPI · 2024Article
- Canalizing cell fate by transcriptional repression.Molecular systems biology · 2024Review
- Worldwide cohort study of 46, XY differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants.Frontiers in genetics · 2024Review
- Single-cell analysis of the developing human ovary defines distinct insights into ovarian somatic and germline progenitors.Developmental cell · 2023Article
- PRC1 suppresses a female gene regulatory network to ensure testicular differentiation.Cell death & disease · 2023Article
- Cell type-specific role of CBX2 and its disordered region in spermatogenesis.Genes & development · 2023Article
- From Enrico Sertoli to freemartinism: the many phases of the master testis-determining cell†.Biology of reproduction · 2023Review
- CDYL reinforces male gonadal sex determination through epigenetically repressingProceedings of the National Academy of Sciences of the United States of America · 2023Article
- In vitro cellular reprogramming to model gonad development and its disorders.Science advances · 2023Article
- Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development.Frontiers in cell and developmental biology · 2023Article
- Loss of WNT4 in the gubernaculum causes unilateral cryptorchidism and fertility defects.Development (Cambridge, England) · 2022Article
- Transgenic Mouse Models to Study the Development and Maintenance of the Adrenal Cortex.International journal of molecular sciences · 2022Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway. To investigate this possibility, we developed a quantitative genome-wide profile of the repressive histone mark H3K27me3 and its active counterpart H3K4me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that testis and ovary sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue testis development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development.
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