Abstract
Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells’ identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
Highlights
Mammalian male germ cell development is a stepwise cell-fate transition process; the full-term developmental profile of male germ cells remains undefined
In accordance with the abnormal developmental trajectory of primordial germ cell (PGC) in Helq−/− mice, we found that the expression dynamics of the three categories of genes, which were necessary for the proper cell-fate transition from mitotic to post-arrest PGCs, were dysregulated (Fig. 5k)
A fundamental question in developmental biology is how mammalian PGCs are specified from the post-implantation epiblasts and how these cells sequentially transit in a stepwise manner to become mature sperm
Summary
Mammalian male germ cell development is a stepwise cell-fate transition process; the full-term developmental profile of male germ cells remains undefined. A single-cell transcriptome atlas to compare mouse and human male germ cell development programs is instructive to uncover evolutionarily conserved regulators. These insights are crucial to recapitulate the complete male gametogenesis process in vitro. The biological function of mitotic to mitotic arrest transition of male PGCs was further verified using Helq knockout mouse model, wherein DNA damage-associated cell-cycle regulation was found to be essential for prenatal development of male germ cells, as exemplified by the involvement of HELQ in controlling the normal development of transitional PGCs and post-arrest PGCs as well as proper transcriptome reconfiguration. To enable public access to our data, we constructed the mouse male germ cell landscape website at https:// tanglab.shinyapps.io/Mouse_Male_Germ_Cells/
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