Genetic Control of Gonadal Sex Determination and Development

New technologies in molecular biology, such as single-cell RNA sequencing and epigenetic techniques, are emerging and being refined at a fast pace. They provide an opportunity to gain new insights into mechanisms driving the fate of progenitor cells and the transcriptional epigenetic dynamics underlying the process of sex determination. A single multipotent progenitor cell population undergoes fate restriction and differentiates into either the supporting or the interstitial/stromal progenitors of the gonad. The supporting cells differentiate from these early progenitors in two sequential steps with first a commitment toward the supporting-cell lineage followed by sex-specific differentiation toward pregranulosa and Sertoli cells. Accumulating evidence suggests that epigenetic mechanisms contribute to establish the male fate. The expression of the male determining gene Sry is regulated by histone modification and DNA methylation. Sex determination is the process by which the bipotential gonads develop as either testes or ovaries. With two distinct potential outcomes, the gonadal primordium offers a unique model for the study of cell fate specification and how distinct cell populations diverge from multipotent progenitors. This review focuses on recent advances in our understanding of the genetic programs and epigenetic mechanisms that regulate gonadal sex determination and the regulation of cell fate commitment in the bipotential gonads. We rely primarily on mouse data to illuminate the complex and dynamic genetic programs controlling cell fate decision and sex-specific cell differentiation during gonadal formation and gonadal sex determination. Sex determination is the process by which the bipotential gonads develop as either testes or ovaries. With two distinct potential outcomes, the gonadal primordium offers a unique model for the study of cell fate specification and how distinct cell populations diverge from multipotent progenitors. This review focuses on recent advances in our understanding of the genetic programs and epigenetic mechanisms that regulate gonadal sex determination and the regulation of cell fate commitment in the bipotential gonads. We rely primarily on mouse data to illuminate the complex and dynamic genetic programs controlling cell fate decision and sex-specific cell differentiation during gonadal formation and gonadal sex determination. a rapid and sensitive technique to assess genome-wide chromatin accessibility. It can help to identify accessible DNA regions equivalent to DNase I hypersensitive sites. This method probes DNA accessibility with hyperactive Tn5 transposase, which inserts sequencing adapter sequences into accessible regions. identifies the genome-wide binding sites of DNA-associated proteins by combining chromatin immunoprecipitation (ChIP) with next-generation sequencing. In particular, a profile of the chromatin landscape in a particular cell type can be obtained from ChIP-seq for histone modifications indicative of active (H3K4me2/3, H3K27ac, H3K9ac, H4K16ac) or silenced (H3K27me3, H3K9me2/3) gene promoters. refers to the epithelium that lines the surface of the body wall and abdominal organs, including the outermost layer of the male and female gonads. Proliferation and delamination of these epithelial cells into the inner mesenchymal region of the mesonephros give rise to the somatic lineage precursors of the urogenital ridges. congenital conditions associated with atypical development of chromosomal, gonadal, or anatomical sex. A small portion of these disorders affects gonad development and differentiation, including 46,XX testicular DSD and 46,XY DSD with partial or complete gonadal dysgenesis. Currently, the majority of DSD patients with gonadal defects do not receive a genetic diagnosis. refers to a technique for genome-wide sequencing of regions exhibiting DNase I hypersensitivity. DNase I hypersensitive sites are regions of chromatin where the genetic material is sensitive to cleavage by the endonuclease. They include promoters, enhancers, insulators, silencers, and other features related to transcriptional activity. the study of heritable changes in gene expression that do not involve changes in the DNA sequence of the genome. Epigenetic marks include histone protein modifications, such as methylation, acetylation, and phosphorylation, and DNA cytosine modifications, such as methylation. the precursors of the gonads; also known as bipotential gonads. They develop as paired thickening layers on the ventral surface of the mesonephroi at around embryonic day E9.5 in mouse embryos. The genital ridges form through the proliferation of the CE and the thickening of the underlying mesonephroi. refers to the developmental decision that directs the bipotential gonad or genital ridge to develop into a testis or an ovary. Once differentiated, the gonads produce sex hormones that promote the development of sexually dimorphic structures that characterize male and female. also known as testis-determining factor (TDS); a member of the SOX protein family of transcription factors. Sry acts as the master gene that initiates male sex determination in almost all mammals by upregulating Sox9 expression and initiating the differentiation of supporting progenitors into Sertoli cells. provides the transcriptional profile of individual cells. By profiling the transcriptome of thousands of individual cells, scRNA-seq provides an atlas of every cell type present in a particular tissue, including rare occurrences. In addition, when performed in time series it allows the reconstruction of cell developmental trajectories and provides transcriptional dynamics occurring during cell lineage commitment and differentiation. play a crucial role during the process of sex determination. In the presence of a Y chromosome carrying the male-determining gene Sry, progenitors from the supporting lineage will differentiate as pre-Sertoli cells and testis will form. In the presence of two X chromosomes, they will commit toward the granulosa fate and an ovary will develop. The term supporting cells refers to the role of the Sertoli and the granulosa cells in nursing and sustaining the development of the gametes.