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. 2017 Apr;144(Pt B):125-139. doi: 10.1016/j.mod.2017.03.002. Epub 2017 Mar 22.
Spermatogenesis is a continuous and highly coordinated process of spermatozoa production. In mice, this process is believed to initiate shortly after birth with the emergence of nascent spermatogonia in the testes. However, because the nascent spermatogonia originated from the gonocytes are morphologically indistinguishable from their predecessors and there is no clear definition for the gonocytes-to-spermatogonia transition (GST), it remains unclear when and how spermatogenesis is initiated in the mouse testes. To address these questions, we characterized the emergence of nascent spermatogonia in ICR mice. We found that GST is initiated in a subset of gonocytes as early as E18.5. These nascent spermatogonia express markers typical of undifferentiated spermatogonia residing in testes of adult mice. In addition to markers expression, we identified FOXO1 nuclear-to-cytoplasmic translocation as a novel feature of GST distinguishing nascent spermatogonia from the gonocytes. Using those criteria, we demonstrated that GST requires FGF signaling. When FGF signaling was inhibited pharmacologically, gonocytes retained nuclear FOXO1 expression, did not express spermatogonial markers and failed to proliferate. We found that FGF signaling acts upstream of GDNF and RA signalings for the activation of the MEK/ERK and PI3K/Akt pathways in germ cells during GST. Taken together, we defined the precise timing of GST and revealed FGF signaling as a master regulator of GST in the perinatal mouse testes.
精子发生是精子产生的一个连续且高度协调的过程。在小鼠中，这个过程被认为在出生后不久就开始了，此时睾丸中出现了新生精原细胞。然而，由于新生精原细胞起源于性原细胞，其形态与前体细胞无法区分，并且性原细胞向精原细胞的过渡（GST）没有明确的定义，因此仍然不清楚精子发生是何时以及如何在小鼠睾丸中开始的。为了解决这些问题，我们对 ICR 小鼠中新生精原细胞的出现进行了特征描述。我们发现，GST 早在 E18.5 就已经在一部分性原细胞中启动。这些新生精原细胞表达典型的未分化精原细胞标志物，存在于成年小鼠的睾丸中。除了标志物表达外，我们还发现 FOXO1 核质易位是 GST 的一个新特征，可将其与性原细胞区分开来。利用这些标准，我们证明 GST 需要 FGF 信号。当 FGF 信号被药理学抑制时，性原细胞保留核 FOXO1 表达，不表达精原细胞标志物，并且无法增殖。我们发现，FGF 信号在 GST 期间作用于 GDNF 和 RA 信号的上游，激活生殖细胞中的 MEK/ERK 和 PI3K/Akt 途径。总之，我们确定了 GST 的精确时间，并揭示了 FGF 信号是围产期小鼠睾丸中 GST 的主要调节因子。
