Dissecting Cell Lineage Specification and Sex Fate Determination in Gonadal Somatic Cells Using Single-Cell Transcriptomics

Sex determination is a unique process that allows the study of multipotent progenitors and their acquisition of sex-specific fates during differentiation of the gonad into a testis or an ovary. Using time series single-cell RNA sequencing (scRNA-seq) on ovarian Nr5a1-GFP+ somatic cells during sex determination, we identified a single population of early progenitors giving rise to both pre-granulosa cells and potential steroidogenic precursor cells. By comparing time series single-cell RNA sequencing of XX and XY somatic cells, we provide evidence that gonadal supporting cells are specified from these early progenitors by a non-sex-specific transcriptomic program before pre-granulosa and Sertoli cells acquire their sex-specific identity. In XX and XY steroidogenic precursors, similar transcriptomic profiles underlie the acquisition of cell fate but with XX cells exhibiting a relative delay. Our data provide an important resource, at single-cell resolution, for further interrogation of the molecular and cellular basis of mammalian sex determination. [Display omitted] •XX Nr5a1+ progenitors give rise to pre-granulosa and steroidogenic precursor cells•Supporting lineages commit similarly with the exception of Sry in XY cells•Sertoli and granulosa cell differentiation is temporally asymmetric•XY and XX progenitors progressively acquire a steroidogenic precursor fate Using single-cell RNA sequencing of Nr5a1-expressing gonadal somatic cells during female and male sex determination, Stévant et al. deconvoluted the cell lineage specification process and sex-specific differentiation of both the supporting and the steroidogenic cell lineages at a transcriptomic level.