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Otx2 的差异抑制是 NANOG 和 ESRRB 诱导生殖细胞进入的能力的基础。

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry.

机构信息

Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, Scotland.

Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China; Guangzhou Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou, 510005, Guangdong Province, China.

出版信息

Stem Cell Reports. 2022 Jan 11;17(1):35-42. doi: 10.1016/j.stemcr.2021.11.013. Epub 2021 Dec 30.

DOI:10.1016/j.stemcr.2021.11.013
PMID:34971561
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8758940/
Abstract

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.

摘要

原始生殖细胞 (PGC) 起源于着床后胚外细胞，对细胞因子信号作出反应。通过细胞因子暴露，将类胚外细胞 (EpiLC) 分化为类原始生殖细胞 (PGCLC)，可在体外重现 PGC 发育。有趣的是，转录因子 (TF) NANOG 的强制表达可以绕过 PGCLC 诱导所需的细胞因子。然而，其潜在机制尚未完全阐明。在这里，我们表明 NANOG 在没有细胞因子的情况下介导 Otx2 的下调，并且这对于 NANOG 诱导 PGCLC 是必不可少的。此外，直接的 NANOG 靶基因 Esrrb 可以替代几个 NANOG 功能，但在 EpiLC 中过表达时不会下调 Otx2，也不能促进 PGCLC 特化。然而，在 Otx2 EpiLC 中表达 ESRRB 可挽救 PGCLC 的出现。这项研究阐明了在 PGC 特化的最早阶段发生的 TFs 相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/397d8ea4bc85/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/c9bb631a1742/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/7449ce770bbc/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/d789f2d5010d/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/397d8ea4bc85/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/c9bb631a1742/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/7449ce770bbc/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/d789f2d5010d/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49a5/8758940/397d8ea4bc85/gr4.jpg

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本文引用的文献

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Direct repression of Nanog and Oct4 by OTX2 modulates the contribution of epiblast-derived cells to germline and somatic lineage.OTX2对Nanog和Oct4的直接抑制作用调节了上胚层来源细胞对生殖系和体细胞谱系的贡献。
Development. 2021 May 15;148(10). doi: 10.1242/dev.199166. Epub 2021 May 13.
2
An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions.一个由前馈环相互作用控制的Esrrb和Nanog细胞命运调控模块。
Front Cell Dev Biol. 2021 Mar 19;9:630067. doi: 10.3389/fcell.2021.630067. eCollection 2021.
3
Segregation of the mouse germline and soma.
鼠生殖细胞与体细胞的分离。
Cell Cycle. 2019 Nov;18(22):3064-3071. doi: 10.1080/15384101.2019.1672466. Epub 2019 Oct 4.
4
The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells.Nanog 诱导小鼠胚胎干细胞自我更新的分子逻辑。
Nat Commun. 2019 Mar 7;10(1):1109. doi: 10.1038/s41467-019-09041-z.
5
OTX2 restricts entry to the mouse germline.OTX2 限制进入小鼠生殖系。
Nature. 2018 Oct;562(7728):595-599. doi: 10.1038/s41586-018-0581-5. Epub 2018 Oct 3.
6
Esrrb Complementation Rescues Development of Nanog-Null Germ Cells.Esrrb 互补作用挽救了 Nanog 缺失的生殖细胞的发育。
Cell Rep. 2018 Jan 9;22(2):332-339. doi: 10.1016/j.celrep.2017.12.060.
7
Functional Antagonism between OTX2 and NANOG Specifies a Spectrum of Heterogeneous Identities in Embryonic Stem Cells.OTX2 和 NANOG 之间的功能拮抗作用在胚胎干细胞中指定了一系列异质的身份。
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8
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