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KDM6B is a conserved activator at the top of the male sex determination pathway

ABSTRACT: In mammals, commitment to the testis fate is controlled by the gene Sry on the Y chromosome; however, how Sry is regulated is not well understood. In the red-eared slider turtle, Dmrt1 acts as the primary activator of the testis pathway. Removal of the repressive histone modification H3K27me3 from Dmrt1 by the histone demethylase KDM6B is required for its activation. We hypothesized that a similar de-repression mechanism is utilized in mammals to activate the testis pathway. Using a mouse knock-out model for Kdm6b, we found that loss of Kdm6b leads to a delay in Sry activation and the development of an ovotestis. These results implicate KDM6B as a conserved regulator at the top of the sex determination cascade in both reptiles and mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE295878 | GEO | 2025/06/05

REPOSITORIES: GEO

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Project description:Gonadal sex differentiation – testis versus ovary formation – is a fundamental process required for reproduction and evolution. Reflecting this importance, the embryonic gonads of vertebrate species comprise the same key cell types; germ cells, supporting cells and interstitial steroidogenic cells. Remarkably, the genetic triggers for gonadal sex differentiation vary across species (the SRY gene in mammals, DMRT1 in birds and some turtles, temperature in many reptiles, AMH and various other genes in fishes). Despite this variation, the cell biology of gonadal development was long thought to be largely conserved. Here, we present a comprehensive analysis of gonadal sex differentiation, using the chicken embryo as a model and considering the entire gonad. We sampled over 30,000 cells across several developmental stages, prior, during and after the onset of gonadal sex differentiation. The data provide several new insights into cell lineage specification during vertebrate gonadogenesis. Combining lineage tracing with single cell transcriptomics, the data show that somatic supporting cells of the embryonic chicken gonad do not derive from the coelomic epithelium, in contrast to other vertebrates studied. Instead, the early somatic precursors cells of the gonads in both sexes derive from a DMRT1+/PAX2+/WNT4+/OSR1+ mesenchymal cell population. In particular, PAX2 marks immigrating mesenchymal cells that give rise to the supporting cell lineage. We find a greater complexity of gonadal cell types than previously thought, including the identification of two distinct sub-populations of Sertoli cells in developing testes, and derivation of embryonic steroidogenic cells from a differentiated supporting cell lineage. We provide significantly improved resolution of gonadal cell types and identify several new gonadal marker genes. Altogether, these results indicate that, just as the genetic trigger for sex differs across vertebrate groups, cell lineage specification in the gonad may also vary substantially.

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KDM6B is a conserved activator at the top of the male sex determination pathway

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