Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry.
Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry.
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DOI：
10.1016/j.stemcr.2021.11.013
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发表时间：
2022-01-11
影响因子：
5.9
通讯作者：
Chambers I
中科院分区：
文献类型：
--
作者：
Vojtek M;Zhang J;Sun J;Zhang M;Chambers I
原始生殖细胞（PGCs）来自着床后上胚层的细胞，响应于细胞因子信号传导。PGC发育可以通过细胞因子暴露将上胚层样细胞（EpiLC）分化为PGC样细胞（PGCLC）在体外重演。有趣的是，PGCLC诱导的细胞因子需求可以通过转录因子（TF）NANOG的强制表达来绕过。然而，其潜在机制尚未完全阐明。在这里，我们表明，NANOG介导的Otx 2下调的情况下，细胞因子，这是必不可少的PGCLC诱导NANOG。此外，直接的NANOG靶基因Esrrb，它可以取代几个NANOG功能，不下调Otx 2时，在EpiLC过表达，不能促进PGCLC规范。然而，在Otx 2 +/− EpiLC中ESRRB的表达拯救了PGCLC的出现。这项研究阐明了在PGC规范的最早阶段发生的TF的相互作用。NANOG过表达通过抑制Otx 2诱导无嘌呤PGCLC特化增强的OTX 2表达防止NANOG诱导的种系进入ESRRB过表达不能抑制Otx 2或诱导无嘌呤种系进入Otx 2杂合性使ESRRB能够诱导无嘌呤PGCLC特化Vojtek和同事表明NANOG抑制Otx 2以诱导原始生殖细胞样细胞（PGCLC）的无嘌呤特化。OTX 2水平对于PGCLC诱导至关重要，因为持续的OTX 2表达阻止NANOG诱导的分化。虽然ESRRB可以在其他过程中功能性地替代NANOG，但ESRRB不抑制Otx 2，并且不能诱导无精氨酸的PGCLC特化，除非Otx 2表达减半。
Primordial germ cells (PGCs) arise from cells of the post-implantation epiblast in response to cytokine signaling. PGC development can be recapitulated in vitro by differentiating epiblast-like cells (EpiLCs) into PGC-like cells (PGCLCs) through cytokine exposure. Interestingly, the cytokine requirement for PGCLC induction can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that NANOG mediates Otx2 downregulation in the absence of cytokines and that this is essential for PGCLC induction by NANOG. Moreover, the direct NANOG target gene Esrrb, which can substitute for several NANOG functions, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, expression of ESRRB in Otx2+/− EpiLCs rescues emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification. NANOG overexpression induces cytokine-free PGCLC specification by repressing Otx2 Enforced OTX2 expression prevents NANOG-induced germline entry ESRRB overexpression cannot repress Otx2 or induce cytokine-free germline entry Otx2 heterozygosity enables ESRRB to induce cytokine-free PGCLC specification Vojtek and colleagues show that NANOG represses Otx2 to induce cytokine-free specification of primordial germ cell-like cells (PGCLCs). OTX2 levels are critical for PGCLC induction, as sustained OTX2 expression prevents NANOG-induced differentiation. Although ESRRB can functionally substitute for NANOG in other processes, ESRRB does not repress Otx2 and cannot induce cytokine-free PGCLC specification unless the Otx2 expression is halved.
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OTX2限制了进入鼠标种系的输入。
影响因子：
64.8
作者：
Zhang J;Zhang M;Acampora D;Vojtek M;Yuan D;Simeone A;Chambers I
通讯作者：
Chambers I
DOI：
10.1073/pnas.130192197
发表时间：
2000-07-05
影响因子：
11.1
作者：
Urlinger, S;Baron, U;Hillen, W
通讯作者：
Hillen, W
影响因子：
10.5
作者：
Lawson, KA;Dunn, NR;Hogan, BLM
通讯作者：
Hogan, BLM
影响因子：
2.6
作者：
Mitsunaga, K;Araki, K;Abe, K
通讯作者：
Abe, K
ESRRB互补挽救了纳米无效生殖细胞的发展。
影响因子：
8.8
作者：
Zhang M;Leitch HG;Tang WWC;Festuccia N;Hall-Ponsele E;Nichols J;Surani MA;Smith A;Chambers I
通讯作者：
Chambers I