Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Abstract

The gonads are unique among the body’s organs in having a developmental choice: testis or ovary formation. Gonadal sex differentiation involves common progenitor cells that form either Sertoli and Leydig cells in the testis or granulosa and thecal cells in the ovary. Single-cell analysis is now shedding new light on how these cell lineages are specified and how they interact with the germline. Such studies are also providing new information on gonadal maturation, ageing and the somatic-germ cell niche. Furthermore, they have the potential to improve our understanding and diagnosis of Disorders/Differences of Sex Development (DSDs). DSDs occur when chromosomal, gonadal or anatomical sex are atypical. Despite major advances in recent years, most cases of DSD still cannot be explained at the molecular level. This presents a major pediatric concern. The emergence of single-cell genomics and transcriptomics now presents a novel avenue for DSD analysis, for both diagnosis and for understanding the molecular genetic etiology. Such -omics datasets have the potential to enhance our understanding of the cellular origins and pathogenesis of DSDs, as well as infertility and gonadal diseases such as cancer.

Establishing and maintaining fertility: the importance of cell cycle arrest

“…These trigger other cell types, including the steroidogenic cells, germ cells, and connective tissue cells, to follow the testicular or ovarian pathway, thereby shaping the gonad and laying the foundations for future reproductive capacity. A failure of the gonads to develop as either XX ovaries or XY testes leads to infertility and disorders/differences of sex development (DSDs), often associated with infertility (Eozenou et al 2020;Estermann and Smith 2020). The gene regulatory networks relevant to sex determination in mice are detailed in several previous reviews (Jakob and Figure 3.…”

“…The advent of novel sequencing technologies such as single-cell RNA sequencing (scRNA-seq), chromatin immu-noprecipitation sequencing (ChIP-seq), and assay for transposase-accessible chromatin sequencing (ATACseq) has accelerated our knowledge of the fundamental genes controlling many developmental processes Nef 2018, 2019;Estermann and Smith 2020;Tam and Ho 2020). These techniques have been applied, primarily in mice, to unravel the initiation of sex-determining pathways in mammalian gonads (Jameson et al 2012;Garcia-Moreno et al 2018;.…”

Gonadal Sex Differentiation: Supporting Versus Steroidogenic Cell Lineage Specification in Mammals and Birds

“…transcript profiling among cells, this approach allows the identification of novel cell type markers as well as defining the origins and developmental trajectories of cell lineages (Stevant and Nef, 2018;Estermann and Smith, 2020). In the mouse, pseudotime reconstruction based on single-cell RNA-seq data reveals that the supporting and steroidogenic progenitors indeed both derive from a coelomic epithelial population with a Nr5a1 + /Nr2f2 + /Sox11 + transcriptional signature.…”

Ambiguous genitalia: clinical management of adult female with male assigned gender: a case report

“…DSDs are associated with atypical development of the internal and external genital structures as a result of variations in genes, developmental programming, and hormones [ 3 ]. DSDs occur when chromosomal, gonadal, or anatomical sex is atypical [ 4 , 5 ], and before 2006, DSD was termed as intersex [ 2 ]. Based on the karyotype, three main groups of DSDs are identified using the new nomenclature proposed by the Chicago Consensus (Table 1 ).…”

“…Disorders of sex development are a major pediatric issue, accounting for approximately 1% of all live births [ 5 ]. However, the incidence varies between developed and developing countries [ 6 ].…”