Cell-fate transition and determination analysis of mouse male germ cells throughout development

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.

Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis

“…7 A, Supplemental Table S9 ). Gene expression analysis revealed that ATRA significantly differentially regulated the expression of 231 germ cell development genes that were identified in a recent single-cell RNA-seq publication ( Zhao et al, 2021 ). Specifically, ATRA upregulated genes first expressed during germ cell development stages, including peaks of DEGs associated with the quiescent prospermatogonia, differentiating and differentiated spermatogonia, and pachytene spermatocyte stages.…”

“…7 ATRA and MEHP altered the transcriptional profile of genes first expressed during germ cell development stages. A. Germ cell-specific gene expression clusters were extracted from Zhao et al (2021) , and are displayed on the x-axis in order of developmental stage. DEG lists for each of the three RNA-seq analyses reported in this paper (MEHP vs vehicle, ATRA vs vehicle, and MEHP + ATRA vs vehicle) were searched for genes first expressed in any germ cell RNA-seq cluster, and the number of genes up- or downregulated per cluster is displayed on the chart.…”

“…It is known that ATRA induces germ cell differentiation and meiosis ( Bowles and Koopman, 2007 , Koubova et al, 2014 , Koubova et al, 2006 ), which is likely to be detrimental to germ cells that are not competent for meiosis. Beyond germ cell survival, to determine whether ATRA and MEHP altered germ cell function and development, we compared the lists of DEGs from our RNA-seq analysis with a list of male germ cell genes and the stages of development when they are first expressed from a recent single-cell RNA-seq study ( Zhao et al, 2021 ) ( Fig. 7 ).…”

“…The goa_MusMusculus GO list was used to cluster the set of genes, categorizing them based on the biological processes. To analyze the effect of our treatments on fetal testicular germ cell development, we compared our DEG lists to germ cell stage-specific single cell RNA-seq data ( Zhao et al, 2021 ). We categorized each gene by the developmental stage (“cluster”) when it is first expressed, as identified in the single-cell RNA-seq data.…”

Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

“…Due to the high heterogeneity and low cell number of ProSG and SSCs, it is challenging to study their characteristics (Du et al, 2021;Tan et al, 2020b). Although several studies have been devoted to distinguishing their subtypes and identifying some subtypes of ProSG and SSCs, much is still unknown about their subtypes (Guo et al, 2018;Guo et al, 2017;Guo et al, 2021;Tan et al, 2020b;Tan and Wilkinson, 2020;Zhao et al, 2021). In this study, we identi ed three cell types using the scRNA-seq technique: ProSG, SSCs, and differentiating spermatogonia.…”