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Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis. [Display omitted] • Comprehensive single-cell transcriptome atlas of normal human male germline development • Transcriptional and open chromatin landscape of seminoma mapped to normal male germline • Altered germline programs, angiogenesis, and MAP kinase signaling pathways in seminoma • An in vitro model of the shaping of seminoma transcriptional programs by isochromosome 12p Cheng et al. map the single-cell transcriptome and open chromatin landscape of seminoma onto their newly established trajectory of human male germline development. They find that seminoma resembles premigratory/migratory primordial germ cells, and they identify alterations in germline programs and MAP kinase signaling that may be influenced by isochromosome 12p. [ABSTRACT FROM AUTHOR]

In the early fetal stage, the gonads are bipotent and only later become the ovary or testis, depending on the genetic sex. Despite many studies examining how sex determination occurs from biopotential gonads, the spatial and temporal organization of bipotential gonads and their progenitors is poorly understood. Here, using lineage tracing in mice, we find that the gonads originate from a T+ primitive streak through WT1+ posterior intermediate mesoderm and appear to share origins anteriorly with the adrenal glands and posteriorly with the metanephric mesenchyme. Comparative single-cell transcriptomic analyses in mouse and cynomolgus monkey embryos reveal the convergence of the lineage trajectory and genetic programs accompanying the specification of biopotential gonadal progenitor cells. This process involves sustained expression of epithelial genes and upregulation of mesenchymal genes, thereby conferring an epithelial-mesenchymal hybrid state. Our study provides key resources for understanding early gonadogenesis in mice and primates. [Display omitted] • Ontogeny of the gonads in mice and monkeys defined by single-cell transcriptomics • Temporally distinct contribution of T+ descendants to the gonads and related organs • The gonads originate from the T+ primitive streak through posterior intermediate mesoderm • The gonads acquire an epithelial-mesenchymal hybrid state upon specification Sasaki et al. map the ontogenic ancestries of the gonads in mice and monkeys. Remarkably, the gonads originate from a T+ primitive streak through WT1+ posterior intermediate mesoderm, and this process involves sustained expression of epithelial genes and upregulation of mesenchymal genes, thereby conferring an epithelial-mesenchymal hybrid state. [ABSTRACT FROM AUTHOR]

Summary The germ cell lineage ensures reproduction and heredity. The mechanism for germ cell specification in primates, including humans, has remained unknown. In primates, upon implantation the pluripotent epiblast segregates the amnion, an extra-embryonic membrane eventually ensheathing an embryo, and thereafter initiates gastrulation to generate three germ layers. Here, we show that in cynomolgus monkeys, the SOX17/TFAP2C/BLIMP1-positive primordial germ cells (cyPGCs) originate from the dorsal amnion at embryonic day 11 (E11) prior to gastrulation. cyPGCs appear to migrate down the amnion and, through proliferation and recruitment from the posterior amnion, expand in number around the posterior yolk sac by E17. Remarkably, the amnion itself expresses BMP4 and WNT3A, cytokines potentially critical for cyPGC specification, and responds primarily to them. Moreover, human PGC-like cells in vitro exhibit a transcriptome similar to cyPGCs just after specification. Our study identifies the origin of PGCs and a unique function of the nascent amnion in primates. [ABSTRACT FROM AUTHOR]

The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we recapitulate human fetal adrenal cortex specification processes through stepwise induction of human-induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenocortical progenitor-like states to ultimately generate fetal zone adrenal-cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN, and WNT signaling, and steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of Δ5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro , paving the way for cell-based therapies of adrenal insufficiency. [Display omitted] • Fetal zone adrenal-cortex-like cells are induced from human pluripotent stem cells • Induction is ACTH independent and inhibited by NOTCH, ACTIVIN, and WNT signaling • Robust Δ5 adrenal steroid biosynthesis is ACTH/PKA-responsive • NR5A1 is essential for survival and steroidogenesis of human fetal adrenal cortex Human adrenocortical development remains enigmatic due to the lack of appropriate models. Adrenocortical lineages established from human pluripotent stem cells by Sakata et al. recapitulate functional, histomorphologic, and transcriptomic features found in vivo , supporting their use for pharmacologic, genetic, and epigenetic interrogation of human adrenocortical development and testing of cell-based therapies. [ABSTRACT FROM AUTHOR]