Abstract
The human germ cell lineage originates from primordial germ cells (PGCs), which are specified at approximately the third week of development. Our understanding of the signaling pathways that control this event has significantly increased in recent years and that has enabled the generation of PGC-like cells (PGCLCs) from pluripotent stem cells in vitro. However, the signaling pathways that drive the transition of PGCs into gonia (prospermatogonia in males or premeiotic oogonia in females) remain unclear, and we are presently unable to mimic this step in vitro in the absence of gonadal tissue. Therefore, we have analyzed single-cell transcriptomics data of human fetal gonads to map the molecular interactions during the sex-specific transition from PGCs to gonia. The CellPhoneDB algorithm was used to identify significant ligand–receptor interactions between germ cells and their sex-specific neighboring gonadal somatic cells, focusing on four major signaling pathways WNT, NOTCH, TGFβ/BMP, and receptor tyrosine kinases (RTK). Subsequently, the expression and intracellular localization of key effectors for these pathways were validated in human fetal gonads by immunostaining. This approach provided a systematic analysis of the signaling environment in developing human gonads and revealed sex-specific signaling pathways during human premeiotic germ cell development. This work serves as a foundation to understand the transition from PGCs to premeiotic oogonia or prospermatogonia and identifies sex-specific signaling pathways that are of interest in the step-by-step reconstitution of human gametogenesis in vitro.
Highlights
Understanding the germ cell life cycle requires identification of the key signaling events that decide and regulate each step of germ cell fate
In the male set (Figure 1A), clusters1–4 represented germ cells, with cells in mCL1 and mCL2 corresponding to primordial germ cells (PGCs) (POU5F1, SOX17, PDPN, PRDM1, and NANOS3) and mCL4 to SGONs, expressing high levels of DDX4, as well as male-specific germ cell markers such as MAGEA3, MAGEB2, PAGE5, and VCX3 and no POU5F1 (Lahn and Page, 2000; Simpson et al, 2005; Lee and Potts, 2017). mCL3 represented a transitory state between PGCs and SGONs, which we named transitory germ cells (TGCs)
We found that based on receptor–ligand expression analysis, both these interactions occur in human gonadal PGCs and GONs, and these are sustained even after PGC migration
Summary
Understanding the germ cell life cycle requires identification of the key signaling events that decide and regulate each step of germ cell fate This knowledge will be essential to recapitulate gametogenesis in vitro in humans, which is expected to be a powerful tool to study human development and generate treatments for infertility. The signaling pathways involved in PGC specification in vivo remain challenging to investigate; work on human preimplantation blastocysts cultured until day 14 dpf suggests that PGC specification may occur around 12 dpf (Chen et al, 2019; Popovic et al, 2019) and may as well be regulated by BMP and WNT signaling (Tang et al, 2016). SGONs arrest as prospermatogonia until birth, and in females, the OGONs enter meiotic prophase I and arrest in the diplotene stage (dictyate) in primordial follicles
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