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The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry-breaking event is executed through polarization of cells at the 8 cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that mouse embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8 cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8 cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4 cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4 cell stage and polarization at the 8 cell stage, mechanisms of the first lineage allocation that had been considered separate.

Gametogenesis is a complex and sex-specific multistep process during which the gonadal somatic niche plays an essential regulatory role. One of the most crucial steps during human female gametogenesis is the formation of primordial follicles, the functional unit of the ovary that constitutes the pool of follicles available at birth during the entire reproductive life. However, the relation between human fetal germ cells (hFGCs) and gonadal somatic cells during the formation of the primordial follicles remains largely unexplored. We have discovered that hFGCs can form multinucleated syncytia, some connected via interconnecting intercellular bridges, and that not all nuclei in hFGC–syncytia were synchronous regarding meiotic stage. As hFGCs progressed in development, pre-granulosa cells formed protrusions that seemed to progressively constrict individual hFGCs, perhaps contributing to separate them from the multinucleated syncytia. Our findings highlighted the cell–cell interaction and molecular dynamics between hFGCs and (pre)granulosa cells during the formation of primordial follicles in humans. Knowledge on how the pool of primordial follicle is formed is important to understand human infertility.

Embryonic stem cells can be incorporated into the developing embryo and its germ line, but, when cultured alone, their ability to generate embryonic structures is restricted. They can interact with trophoblast stem cells to generate structures that break symmetry and specify mesoderm, but their development is limited as the epithelial–mesenchymal transition of gastrulation cannot occur. Here, we describe a system that allows assembly of mouse embryonic, trophoblast and extra-embryonic endoderm stem cells into structures that acquire the embryo’s architecture with all distinct embryonic and extra-embryonic compartments. Strikingly, such embryo-like structures develop to undertake the epithelial–mesenchymal transition, leading to mesoderm and then definitive endoderm specification. Spatial transcriptomic analyses demonstrate that these morphological transformations are underpinned by gene expression patterns characteristic of gastrulating embryos. This demonstrates the remarkable ability of three stem cell types to self-assemble in vitro into gastrulating embryo-like structures undertaking spatio-temporal events of the gastrulating mammalian embryo. Sozen et al. devise an approach to combine embryonic stem cells, trophoblast stem cells and extra-embryonic endoderm stem cells into self-assembling embryo-like structures, which recapitulate key hallmarks of gastrulation in vitro.

The mouse is the most widely used model organism for studying mammalian gonadal sex determination and related human disorders. However, a systematic and comprehensive comparison of human and mouse sex determination processes is lacking. Here, we performed an interspecies comparative analysis of the single-cell transcriptomic atlas of gonadal sex determination in mice and humans. Our results revealed major transcriptomic differences in each of the major cell types between human and mouse gonads. Only a small fraction of these genes shared a comparable expression profile, often genes known to be essential for gonadal sex determination. While the most differentiated gonadal cell types share similar transcriptomic signatures between humans and mice, poorly differentiated cells, such as somatic progenitors, show more divergent profiles. Ultimately, these comparisons will identify the genes and pathways for which the mouse is a suitable model to study human gonadal abnormalities and optimise the use of animal models.

In the version of this Technical Report originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Report.

During development of the male reproductive tract, the human rete functions as a bridging structure between the seminiferous tubes and the efferent ducts of the epididymis. However, despite its significant contribution to human sex-specific gonadogenesis and future male fertility, the rete testis remains poorly understood. To investigate fetal rete testis development, we have performed single-cell transcriptomics on human fetal testes (and ovaries) and mesonephros/epididymis from first and second trimester. By revealing KRT19 and PAX8 as rete markers, we were able to identify the molecular signatures of the rete epithelial cells and mesonephros/epididymis epithelial cells. In the process, we have identified a population of Sertoli cells and germ cells in the rete testis. Moreover, we also revealed a small population of epithelial cells in the rete ovarii, comparable to the epithelial cells in the rete testis. Together, our study provides insights into human fetal sex-specific gonadogenesis and development of the male reproductive tract beyond the gonads. Competing Interest Statement The authors have declared no competing interest.

The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry breaking event is executed through polarization of cells at the 8-cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8-cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8-cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4-cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4-cell stage and polarization at the 8-cell stage, mechanisms of the first lineage allocation that had been considered separate.