MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, Scotland.
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, United Kingdom.
Cell Rep. 2018 Jan 9;22(2):332-339. doi: 10.1016/j.celrep.2017.12.060.
The transcription factors (TFs) Nanog and Esrrb play important roles in embryonic stem cells (ESCs) and during primordial germ-cell (PGC) development. Esrrb is a positively regulated direct target of NANOG in ESCs that can substitute qualitatively for Nanog function in ESCs. Whether this functional substitution extends to the germline is unknown. Here, we show that germline deletion of Nanog reduces PGC numbers 5-fold at midgestation. Despite this quantitative depletion, Nanog-null PGCs can complete germline development in contrast to previous findings. PGC-like cell (PGCLC) differentiation of Nanog-null ESCs is also impaired, with Nanog-null PGCLCs showing decreased proliferation and increased apoptosis. However, induced expression of Esrrb restores PGCLC numbers as efficiently as Nanog. These effects are recapitulated in vivo: knockin of Esrrb to Nanog restores PGC numbers to wild-type levels and results in fertile adult mice. These findings demonstrate that Esrrb can replace Nanog function in germ cells.
转录因子（TFs）Nanog 和 Esrrb 在胚胎干细胞（ESCs）和原始生殖细胞（PGC）发育中发挥重要作用。Esrrb 是 ESCs 中 Nanog 的正向调控直接靶标，可在 ESCs 中定性替代 Nanog 功能。这种功能替代是否扩展到生殖系尚不清楚。在这里，我们表明生殖系中 Nanog 的缺失会导致中孕期 PGC 数量减少 5 倍。尽管存在这种定量耗竭，但 Nanog 缺失的 PGC 仍能完成生殖系发育，与先前的发现相反。Nanog 缺失的 ESCs 的 PGC 样细胞（PGCLC）分化也受损，Nanog 缺失的 PGCLCs 增殖减少，凋亡增加。然而，Esrrb 的诱导表达同样有效地恢复了 PGCLC 的数量。这些效应在体内得到了重现：Nanog 的 Esrrb 基因敲入将 PGC 数量恢复到野生型水平，并导致可育的成年小鼠。这些发现表明 Esrrb 可以在生殖细胞中替代 Nanog 功能。
