Many germ cells are eliminated during development, long before oogenesis or spermatogenesis. In mouse fetal testes, the majority of germ cell apoptosis coincides with the onset of male differentiation, suggesting coordination of these processes. We studied fetal germ-cell fates and discovered that both apoptosis and differentiation initiate in clonally related clusters. Lineage tracing confirmed that germ cells die as clones independent of intercellular bridges, suggesting that shared intrinsic properties are apoptotic determinants. We identified transcriptional heterogeneity among fetal germ cells that included an apoptosis-susceptible population characterized by failure to differentiate, whereas successful differentiation to prospermatogonia occurred through the expression of epigenetically regulated genes, including LINE1. Our results indicate that the fetal germ-cell fate is based on discrete cell-heritable identities. Elevated DNA methylation in the apoptosis-susceptible subpopulation supports our hypothesis that earlier errors in germ-cell epigenetic reprogramming derail differentiation in cellular progeny, leading to fetal apoptotic selection that ultimately improves the gamete quality.

许多生殖细胞在发育过程中被消除，远在卵子发生或精子发生之前。在小鼠胎儿睾丸中，大多数生殖细胞凋亡与雄性分化的开始同时发生，表明这些过程的协调。我们研究了胎儿生殖细胞的命运，发现细胞凋亡和分化都始于克隆相关的簇。谱系追踪证实生殖细胞作为独立于细胞间桥的克隆而死亡，这表明共有的内在特性是凋亡的决定因素。我们确定了胎儿生殖细胞之间的转录异质性，其中包括以无法分化为特征的细胞凋亡易感群体，而通过表观遗传调节基因的表达成功分化为原精原细胞，包括线1。我们的结果表明，胎儿生殖细胞的命运是基于离散的细胞可遗传特性。细胞凋亡易感亚群中升高的 DNA 甲基化支持我们的假设，即生殖细胞表观遗传重编程中的早期错误会破坏细胞后代的分化，导致最终提高配子质量的胎儿凋亡选择。