Tead4和Tfap2c在全能胚胎中产生双能和双稳态切换，以促进强大的谱系多样化-动脉网

Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification

Nature 等信源发布 2024-05-24 17:48

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AbstractThe mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency.

摘要小鼠和人类胚胎在分化为内细胞团（ICM，未来生物体）和滋养外胚层（TE，未来胎盘）之前逐渐失去全能性。具有活化RHOA的转录因子TFAP2C和TEAD4加速胚胎极化。在这里，我们表明，这些因素也加速了全能性的丧失。

TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate.

TFAP2C和TEAD4在谱系多样化之前矛盾地促进和抑制Hippo信号传导：它们驱动多种Hippo调节剂的表达，同时也促进顶端结构域的形成，从而使Hippo失活。每个因子激活双能细胞中的TE说明符，而TFAP2C也激活ICM命运的说明符。

Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo..

顶端结构域的不对称分离协调了Hippo信号转导到Hippo OFF和TE命运或Hippo ON和ICM命运的相反调节。我们建议利用TFAP2C和TEAD4建立的双稳态开关来触发发育中胚胎中强大的谱系多样化。。

MainIn mammals, the highly differentiated sperm and egg fuse to generate a totipotent zygote that gives rise to all the cells in the body and to the extraembryonic tissues. Totipotency gradually decreases during the first few cell divisions (Fig. 1a). At the eight-cell stage, each cell (blastomere) becomes polarized along the outside–inside axis, forming a cap-shape structure on the outside domain called the apical domain1,2,3,4,5.

在哺乳动物中，高度分化的精子和卵子融合产生全能合子，产生体内所有细胞和胚外组织。在最初的几个细胞分裂过程中，全能性逐渐降低（图1a）。在八细胞阶段，每个细胞（卵裂球）沿内外轴极化，在称为顶端结构域1,2,3,4,5的外部结构域上形成帽状结构。

Asymmetric segregation of apical domains produces a 16-cell embryo with polar outside cells that will become the trophectoderm (TE, future placenta) and apolar inside cells that will become the inner cell mass (ICM, future epiblast and yolk sac)6,7. ICM- and TE-specific transcription factors were found to be co-expressed in blastomeres before lineage diversification4,8,9,10,11,12.

顶端结构域的不对称分离产生具有极性外细胞的16细胞胚胎，其将成为滋养外胚层（TE，未来的胎盘）和非极性内细胞，其将成为内细胞团（ICM，未来的外胚层和卵黄囊）6,7。在谱系多样化之前，发现ICM和TE特异性转录因子在卵裂球中共表达4,8,9,10,11,12。

However, what mechanisms lead to the co-expression of opposite lineage markers and to reconciliation of this bipotency into one of the two fates remain unclear.Fig. 1: Premature expression of TFAP2C, TEAD4 and activated Rho GTPase are sufficient to advance the first cell fate decision.a, A schematic of preimplantation development.

然而，什么机制导致相反谱系标记的共表达以及这种双能性与两种命运之一的协调尚不清楚。图1:TFAP2C，TEAD4和活化的Rho GTPase的过早表达足以推进第一个细胞命运决定。a，植入前发育的示意图。

ZGA, zygotic genome activation. b, A schematic of differential Hippo signalling in TE (top) and ICM (bottom) lineages in the morula stage mouse embryo. c, A schematic of blastocyst reconstruction assay. Two-cell stage embryos injected with Ezrin–RFP (Ezrin only, control) or Tfap2c + Tead4 + RhoA mRNA (TTRhoA) were cultured until the early 16-cell stage.

ZGA，合子基因组激活。b、桑椹胚期小鼠胚胎中TE（顶部）和ICM（底部）谱系中差异Hippo信号传导的示意图。c、胚泡重建测定的示意图。注射Ezrin-RFP（仅Ezrin，对照）或Tfap2c的两细胞期胚胎 + Tead4 + 培养RhoA mRNA（TTRhoA）直至16细胞早期。

Sixteen polarized cells from each genotype were sorted, re-aggregated, cultured until the mid-blastocyst stage and the proportion of ICM examined. d, Representative images of the reconstructed blastocysts from Ezrin-only or TTRhoA embryos. Embryos were immunostained to reveal CDX2 (TE), NAN.

对每种基因型的16个极化细胞进行分选，重新聚集，培养直至囊胚中期，并检查ICM的比例。d、仅来自Ezrin或TTRhoA胚胎的重建胚泡的代表性图像。对胚胎进行免疫染色以显示CDX2（TE），NAN。

Data availability

数据可用性

The bulk RNA-sequencing data of Tfap2c and Tead4 RNAi at the eight-cell stage mouse embryo were deposited as previously described28 (GSE124755). All other raw data for making the graphs in the paper, as well as the raw images used in figures can be found in the Source data and Supplementary information sections in the manuscript.

如前所述28（GSE124755）保存了八细胞期小鼠胚胎中Tfap2c和Tead4 RNAi的大量RNA测序数据。可以在手稿的源数据和补充信息部分找到用于制作本文中图形的所有其他原始数据以及图形中使用的原始图像。

Source data are provided with this paper..

本文提供了源数据。。

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Download referencesAcknowledgementsWe thank all reviewers and A. Andersen from the Life Science Foundation for their constructive comments and extremely valuable suggestions. We thank S. Malas (The Cyprus Institute) for providing the Gata3–GFP transgenic line, C. Graham for helping to process human embryos for immunostaining in University of Oxford and S.

下载参考文献致谢我们感谢所有审稿人和生命科学基金会的A.Andersen提出的建设性意见和极为宝贵的建议。我们感谢S.Malas（塞浦路斯研究所）提供Gata3-GFP转基因品系，C.Graham帮助牛津大学和S。

Junyent Espinosa, W. Hu and Z. Liao for the help in some pilot experiments at Caltech. This work was supported by grants from the Wellcome Trust (098287/Z/12/Z), European Research Council (ERC) (669198), Leverhulme Trust (RPG-2018-085), Open Philanthropy/Silicon Valley, Weston Havens Foundations and National Institutes of Health R01HD100456A to M.Z.-G.

Junyent Espinosa、W.Hu和Z.Liao在加州理工学院的一些试点实验中提供了帮助。这项工作得到了惠康信托基金（098287/Z/12/Z），欧洲研究理事会（ERC）（669198），Leverhulme信托基金（RPG-2018-085），开放慈善/硅谷，韦斯顿港基金会和国立卫生研究院R01HD100456A对M.Z.-G的资助。

Program of China grants 2017YFA0102802 and 2019YFA0110001 to J.N. M.Z. is a Human Frontier Science program long-term fellow. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.Author informationAuthor notesMeng ZhuPresent address: Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USAAuthors and AffiliationsMammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UKMeng Zhu, Maciej Meglicki, Adiyant Lamba & Magdalena Zernicka-GoetzDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USAMeng Zhu, Muhammad Abdullah Jauhar & Magdalena Zernicka-GoetzCentre for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, ChinaPeizhe Wang & Jie NaDepartment of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UKChristophe RoyerOxford Fertility, Institute of Reproductive Sciences, Oxford, UKKaren T.

中国计划向J.N.M.Z.授予2017YFA0102802和2019YFA0111001。是人类前沿科学计划长期研究员。资助者在研究设计，数据收集和分析，决定发表或准备稿件方面没有任何作用。作者信息作者注朱明明目前的地址：美国马萨诸塞州波士顿哈佛医学院布拉瓦尼克研究所遗传学系作者和附属机构剑桥大学生理学，发育与神经科学系哺乳动物胚胎与干细胞组，英国剑桥大学，朱明明，马西吉·梅格里基，阿迪扬特·兰巴和马格达莱娜·泽尼卡·戈茨加利福尼亚理工学院生物与生物工程系，加利福尼亚州帕萨迪纳，朱明明，穆罕默德·阿卜杜拉·贾哈尔和马格达莱娜·泽尼卡·戈茨清华大学医学院干细胞生物学和再生医学中心牛津大学，牛津大学，生理学，解剖学和遗传学，英国克里斯托弗·罗耶，牛津生殖科学研究所，英国卡伦·T。

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PubMed Google ScholarContributionsM.Z. and M.Z.-G. conceived the project. M.Z., M.M., A.L., P.W., C.R. and M.A.J. performed the experiments. M.Z. and P.W. analyzed the data. K.T., C.J., T.C. and K.C. provided the human embryo samples. M.Z.-G. and J.N. supervised the project.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。Z、 M.Z.-G.构思了这个项目。M、 Z.，M.M.，A.L.，P.W.，C.R.和M.A.J.进行了实验。M、 Z.和P.W.分析了数据。K、 T.，C.J.，T.C.和K.C.提供了人类胚胎样本。M、 Z.-G.和J.N.监督了这个项目。对应作者对应。

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Nature Structural & Molecular Biology thanks Jason Knott for their contribution to the peer review of this work. Dimitris Typas was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Nature Structural＆Molecular Biology感谢Jason Knott为这项工作的同行评审做出的贡献。Dimitris Typas是本文的主要编辑，并与其他编辑团队合作管理其编辑过程和同行评审。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Expression of Tfap2c, Tead4 and activated Rho GTPase are sufficient to advance the first cell fate decision.(a) Representative images of the reconstructed blastocysts from Ezrin-only or TTRhoA embryos.

Additional informationPublisher的注释Springer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1 Tfap2c，Tead4和活化的Rho GTPase的表达足以推进第一个细胞命运决定。（a）仅来自Ezrin或TTRhoA胚胎的重建胚泡的代表性图像。

Embryos were immunostained to reveal CDX2 (TE), NANOG (epiblast) and SOX17 (primitive endoderm). Experimental procedures were described as in Fig. 1c. (b) Quantifications of TE and ICM cell numbers in each reconstructed blastocyst generated from experiment described in Fig. 1c. * p = 0.0276; ns, not significant, Two-sided student’s t test.

对胚胎进行免疫染色以显示CDX2（TE），NANOG（外胚层）和SOX17（原始内胚层）。实验程序如图1c所示。（b）从图1c中描述的实验产生的每个重建胚泡中TE和ICM细胞数量的定量。*p = 0.0276；ns，不显着，双面学生t检验。

Each dot indicates the datapoint obtained from one embryo. N = 19 embryos for Ezrin-only group, N = 16 embryos for TTRhoA group. N = 2 experiments. (c) Representative images of embryos injected with Ezrin-RFP or with Tfap2c+Tead4+RhoA mRNA in one cell of the 2-cell stage, and immunostained with DAPI with TFAP2C at the 4–8 cell stage.

每个点表示从一个胚胎获得的数据点。N = 仅Ezrin组的19个胚胎，N = TTRhoA组有16个胚胎。N = 2个实验。（c）在2细胞阶段的一个细胞中注射了Ezrin-RFP或Tfap2c+Tead4+RhoA mRNA的胚胎的代表性图像，并在4-8细胞阶段用DAPI和Tfap2c进行了免疫染色。

(d) Representative images of embryos injected with Ezrin-RFP or with Tfap2c+Tead4+RhoA mRNA at the one cell of the 2-cell stage, and immunostained with DAPI with TEAD4 at the 8-cell stage. (e) Representative images of embryos injected with EZRIN-RFP and dsRNA targeting Tfap2c at the one cell of the 2-cell stage, and immunostained with DAPI with TFAP2C at the 8- stage.

（d）在2细胞阶段的一个细胞中注射了Ezrin-RFP或Tfap2c+Tead4+RhoA mRNA的胚胎的代表性图像，并在8细胞阶段用DAPI和Tead4进行了免疫染色。（e）在2细胞阶段的一个细胞中注射靶向Tfap2c的EZRIN-RFP和dsRNA的胚胎的代表性图像，并在8阶段用DAPI与Tfap2c进行免疫染色。

(f) Representative images of embryos injected with EZRIN-RFP and dsRNA targeting Tead4 at both cells of the 2-cell stage, and immunostained with DAPI with TEAD4 at the 8- stage. N = 2 experiments for c-f. Scale bars, 15 μm.Source dataExtended Data Fig. 2 AMOT protein is tethered to the prematurely formed apical domain by the expression of Tfap2c, Tead4, an.

（f）在2细胞阶段的两个细胞中注射靶向Tead4的EZRIN-RFP和dsRNA的胚胎的代表性图像，并在8阶段用Tead4的DAPI进行免疫染色。N = 2个c-f实验。比例尺，15μm。来源数据扩展数据图2 AMOT蛋白通过Tfap2c，Tead4，an的表达与过早形成的顶端结构域相连。

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Reprints and permissionsAbout this articleCite this articleZhu, M., Meglicki, M., Lamba, A. et al. Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification.

转载和许可本文引用本文Zhu，M.，Meglicki，M.，Lamba，A。等人。Tead4和Tfap2c在全能胚胎中产生双能性和双稳态转换，以促进强大的谱系多样化。

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