Department of Genetics, The Graduate University for Advanced Studies, 1111 Yata, Mishima, 411-8540 Shizuoka, Japan; Division of Mammalian Development, National Institute of Genetics, 1111 Yata, Mishima, 411-8540 Shizuoka, Japan.
Department of Genetics, The Graduate University for Advanced Studies, 1111 Yata, Mishima, 411-8540 Shizuoka, Japan; Division of Mammalian Development, National Institute of Genetics, 1111 Yata, Mishima, 411-8540 Shizuoka, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033 Tokyo, Japan.
Mech Dev. 2018 Feb;149:27-40. doi: 10.1016/j.mod.2018.01.001. Epub 2018 Jan 12.
In the male mouse embryos, the primordial germ cells colonize the developing testes at E11.5. These resident germ cells termed gonocytes are the predecessors of spermatogonial stem cells (SSCs) and differentiating spermatogonia. Both of which are essential for male fertility where the former maintains the continuity of spermatogenesis and the latter generates pioneering waves of spermatozoa. Therefore the timely initiation of gonocytes-to-spermatogonia transition (GST) is an important process during which the cell fates of gonocytes might be segregated. However, it is unknown whether gonocytes are composed of a heterogeneous mixture of germ cells with distinct differentiation potentials during GST. Here, we find that gonocytes exhibit heterogeneity in terms of the expression pattern of at least three early spermatogonial marker genes namely Nanos2, Stra8 and Gfra1. NANOS2 expression levels are negatively correlated with those of STRA8 and GFRA1 before GST, while positive correlation with GFRA1 is established after GST. We further find that overexpression of NANOS2 results in the repression of GFRA1 and PLZF in gonocytes, leading to a delay in GST. On the other hand, loss of NANOS2 results in the up-regulation of GFRA1 and PLZF, indicating a precocious entry of GST. Taken together, our data suggest that NANOS2 functions as an intrinsic timekeeper of GST in the mouse testes.
在雄性小鼠胚胎中，原始生殖细胞于 E11.5 定植于发育中的睾丸中。这些常驻生殖细胞称为精原细胞，是精原干细胞（SSC）和分化精原细胞的前体。两者都是雄性生育力所必需的，前者维持精子发生的连续性，后者产生先驱精子。因此，精原细胞向精原细胞过渡（GST）的及时启动是一个重要过程，在此过程中，精原细胞的细胞命运可能会被分离。然而，尚不清楚 GST 期间精原细胞是否由具有不同分化潜力的异质生殖细胞混合物组成。在这里，我们发现精原细胞在至少三个早期精原细胞标记基因的表达模式上表现出异质性，即 Nanos2、Stra8 和 Gfra1。NANOS2 表达水平在 GST 之前与 STRA8 和 GFRA1 的表达水平呈负相关，而在 GST 之后与 GFRA1 呈正相关。我们进一步发现 NANOS2 的过表达导致精原细胞中 GFRA1 和 PLZF 的抑制，导致 GST 延迟。另一方面，NANOS2 的缺失导致 GFRA1 和 PLZF 的上调，表明 GST 过早进入。总之，我们的数据表明 NANOS2 作为 GST 在小鼠睾丸中的内在定时器发挥作用。
