BMP4对小鼠胚胎和胚胎外发育的时间效应-动脉网

Temporal BMP4 effects on mouse embryonic and extraembryonic development

Nature 等信源发布 2024-09-17 23:17

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AbstractThe developing placenta, which in mice originates through the extraembryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet unbiased characterization of the differentiation dynamics of the ExE and its interactions with the embryo proper remains incomplete. Here we develop a temporal single-cell model of mouse gastrulation that maps continuous and parallel differentiation in embryonic and extraembryonic lineages.

摘要发育中的胎盘起源于胚外外胚层（ExE），对哺乳动物胚胎发育至关重要。然而，ExE的分化动力学及其与胚胎本身的相互作用的无偏表征仍然不完整。在这里，我们开发了小鼠原肠胚形成的时间单细胞模型，该模型绘制了胚胎和胚外谱系中连续和平行的分化。

This is matched with a three-way perturbation approach to target signalling from the embryo proper, the ExE alone, or both. We show that ExE specification involves early spatial and transcriptional bifurcation of uncommitted ectoplacental cone cells and chorion progenitors. Early BMP4 signalling from chorion progenitors is required for proper differentiation of uncommitted ectoplacental cone cells and later for their specification towards trophoblast giant cells.

这与三向扰动方法相匹配，以靶向来自胚胎本身，单独的ExE或两者的信号。我们表明，ExE规范涉及未定型的胎盘外锥细胞和绒毛膜祖细胞的早期空间和转录分叉。绒毛膜祖细胞的早期BMP4信号传导是正确分化未定型的胎盘外锥细胞以及后来向滋养层巨细胞分化所必需的。

We also find biphasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper mesoendoderm bifurcation and for allantois and primordial germ cell specification. However, commencing at embryonic day 7.5, embryo-derived BMP4 restricts the primordial germ cell pool size by favouring differentiation of their extraembryonic mesoderm precursors towards an allantois fate.

我们还发现BMP4在胚胎中具有双相调节作用。早期ExE起源的BMP4信号对于正确的中胚层分叉以及尿囊和原始生殖细胞规格是必需的。然而，从胚胎第7.5天开始，胚胎衍生的BMP4通过促进其胚外中胚层前体向尿囊命运的分化来限制原始生殖细胞库的大小。

ExE and embryonic tissues are therefore entangled in time, space and signalling axes, highlighting the importance of their integrated understanding and modelling in vivo and in vitro..

因此，ExE和胚胎组织在时间，空间和信号轴上纠缠在一起，突出了它们在体内和体外综合理解和建模的重要性。。

MainThe mammalian embryo develops alongside the placenta, a transient organ that constitutes the core infrastructure of the fetomaternal interface that nurtures the embryo until parturition through a constant supply of nutrients and gases, hormone production and immune modulation1. In mice, the embryo and its placenta develop in sync, emerging from the post-implantation blastocyst’s inner cell mass and their adjacent polar trophectoderm cells, respectively2.

。在小鼠中，胚胎及其胎盘同步发育，分别从植入后胚泡的内细胞团及其相邻的极性滋养外胚层细胞中出现2。

The latter gives rise to the ExE lineage, which differentiates to form the stereotypical structure of the mature placenta (Fig. 1a). The most proximal part of the ExE, termed the ectoplacental cone (EPC), gives rise to the outermost regions of the placenta, encompassing the parietal trophoblast giant cells (TGCs), spiral artery TGCs and the spongiotrophoblast and glycogen-accumulating (SpT-Gly) cells situated above and within the junctional zone (JZ)1.

后者产生了ExE谱系，它分化形成成熟胎盘的定型结构（图1a）。ExE的最近端部分，称为胎盘外锥（EPC），产生胎盘的最外层区域，包括顶叶滋养层巨细胞（TGC），螺旋动脉TGC和海绵滋养层和糖原积累（SpT-Gly）位于交界区（JZ）1上方和内部的细胞。

The innermost placental compartment, the labyrinth, constitutes the fetomaternal exchange apparatus. It comprises mostly syncytiotrophoblast cells descendant of the ExE chorion lineage, but also of dilated maternal sinuses, an exclusive TGC cell type3. The labyrinth also features fetal vessels lined by endothelial cells of mesodermal origin4, connected to the fetus through the umbilical cord.

最内层的胎盘隔室迷宫构成胎儿母体交换装置。它主要包括ExE绒毛膜谱系后代的合体滋养层细胞，但也包括扩张的母体鼻窦，这是一种独特的TGC细胞类型3。迷路还具有胎儿血管，其内衬有中胚层起源的内皮细胞4，通过脐带与胎儿相连。

These structures trace their origins to the extraembryonic mesoderm (ExM) lineage.Fig. 1: A unified extraembryonic–embryonic temporal model for gastrulation.a, Illustration of a mature mouse haemochorial placenta, showing the different subcompartments. SpA-TGC, spiral artery TGC; p-TGC, parietal TGC.

这些结构可以追溯到胚外中胚层（ExM）谱系。图1：原肠胚形成的统一胚外-胚胎时间模型。A，成熟小鼠脉络膜胎盘的图示，显示了不同的小室。SpA TGC，螺旋动脉TGC；p-TGC，顶叶TGC。

b, UMAP (uniform manifold approximation and projection) of all embryonic and extraembryonic endoderm cells (n = 57,555 cells, excluding parietal endoderm). The small points represent.

b、所有胚胎和胚外内胚层细胞（n=57555个细胞，不包括顶叶内胚层）的UMAP（均匀流形近似和投影）。小点代表。

Data availability

数据可用性

All sequencing data supporting the conclusions of this study have been meticulously archived and are publicly accessible through the NCBI Gene Expression Omnibus (GEO). These data are catalogued under the GEO Series accession number GSE267870. This ensures comprehensive availability and transparency of the data supporting our research findings.

所有支持这项研究结论的测序数据都经过精心存档，可以通过NCBI基因表达综合（GEO）公开获取。这些数据以GEO系列登录号GSE267870分类。这确保了支持我们研究结果的数据的全面可用性和透明度。

Source data are provided with this paper..

本文提供了源数据。。

Code availability

代码可用性

All custom scripts used in this study have been made openly accessible and can be found at GitHub (https://github.com/tanaylab/EmbExe). Moreover, these scripts have been deposited for permanent archiving and citation at Zenodo71 (https://doi.org/10.5281/zenodo.11240229). This ensures transparency and reproducibility of the computational methods employed in our research..

这项研究中使用的所有自定义脚本都可以公开访问，可以在GitHub上找到(https://github.com/tanaylab/EmbExe)。此外，这些脚本已保存在Zenodo71上进行永久存档和引用(https://doi.org/10.5281/zenodo.11240229)。这确保了我们研究中使用的计算方法的透明度和可重复性。。

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J. Shin, S. J. Schulte and N. A. Pierce for support using multiplex HCR–RNA-FISH. Y.S. is the incumbent of the Louis and Ida Rich Career Development Chair and a member of the European Molecular Biology Organization Young Investigator Program. Research in the Stelzer laboratory is supported by a research grant from the Estate of Betty Weneser, European Research Council (ERC_StG 852865), Helen and Martin Kimmel Stem Cell Institute, ISF (1610/18), Weizmann–Caltech Schwartz/Reisman Collaborative Science Program and Abisch Frenkel Foundation.

J、 Shin，S。J。Schulte和N。A。Pierce使用多重HCR-RNA-FISH进行支持。Y、美国现任路易斯和艾达·里奇职业发展主席，也是欧洲分子生物学组织青年研究员计划的成员。Stelzer实验室的研究得到了Betty Weneser、欧洲研究理事会（ERC\U StG 852865）、Helen and Martin Kimmel干细胞研究所、ISF（1610/18）、Weizmann-Caltech-Schwartz/Reisman合作科学计划和Abisch-Frenkel基金会的研究资助。

This research was also supported by B. and J. Lang, the Hadar Impact Fund, the Lord Sieff of Brimpton Memorial Fund, J. and S. Anixter, J. Silva, Maurice and the Vivienne Wohl Biology Endowment, and the Lester and Edward Anixter Family. Work in the lab of M.B.E. was supported by US National Institutes of Health grant R01 HD075335A and by the Paul G.

这项研究也得到了B.和J.Lang、Hadar冲击基金、布里姆顿纪念基金会的Sieff勋爵、J.和S.Anixter、J.Silva、Maurice和Vivienne Wohl生物基金会以及Lester和Edward Anixter家族的支持。M.B.E.实验室的工作得到了美国国立卫生研究院拨款R01 HD075335A和Paul G。

Allen Frontiers Group and Prime Awarding Agency under award no. UWSC10142. M.Z.-G. is a Bren Professor of Biology and Biological Engeneering and Nomis Foundation Distinguish Fellow and this research in her laboratory was supported by the US National Institutes of Health (R01 HD101489A and DP1 HD104575A).

艾伦边疆集团（Allen Frontiers Group）和主要奖项授予机构，奖项编号为UWSC10142。M、 Z.-G.是布伦生物学和生物工程教授以及诺米斯基金会杰出研究员，她的实验室研究得到了美国国立卫生研究院（R01 HD101489A和DP1 HD104575A）的支持。

The J.H.H. laboratory is funded by Pascal and Ilana Mantoux, the Flight Attendant Medical Research Institute (FAMRI) and the European Union (ERC-CO.

J。H、 H.实验室由Pascal和Ilana Mantoux、空乘医学研究所（FAMRI）和欧盟（ERC-CO）资助。

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PubMed Google ScholarContributionsR.H., H.R., M.M., A.T. and Y.S. conceived and designed the experiments and performed data analysis and its interpretation. S.C., Y.M. and R.B.-Y. assisted in the collection of single cells from individual embryos and N.R. prepared scRNA-seq libraries.

PubMed谷歌学术贡献。H、，H.R.，M.M.，A.T.和Y.S.构思并设计了实验，并进行了数据分析及其解释。S、 C.，Y.M.和R.B.-Y.协助从单个胚胎和N.R.制备的scRNA-seq文库中收集单细胞。

A.L. contributed tools and advice with computational analysis. A.A.C. performed ex utero culture experiments. R.B.-Y. assisted in spatial analysis and microscopy. R.H., A.-H.O. and Y.M. performed transgenic manipulation and animal handling. M.Z.-G. and M.B.E contributed tools and advice with HCR experiments.

A、 L.为计算分析提供了工具和建议。A、 A.C.进行了子宫外培养实验。R、 B.-Y.协助进行空间分析和显微镜检查。R、 H.，A.-H.O.和Y.M.进行了转基因操作和动物处理。M、 Z.-G.和M.B.E为HCR实验提供了工具和建议。

J.H.H. contributed tools and advice with ex utero culture experiments. R.H., H.R., M.M., A.T. and Y.S. wrote the manuscript with input from all of the authors.Corresponding authorsCorrespondence to.

J、 H.H.为子宫外培养实验提供了工具和建议。R、 H.，H.R.，M.M.，A.T.和Y.S.在所有作者的投入下撰写了手稿。通讯作者通讯。

Amos Tanay or Yonatan Stelzer.Ethics declarations

Amos Tanay或Yonatan Stelzer。道德宣言

Competing interests

相互竞争的利益

M.B.E. is a co-founder, scientific advisory board member, or consultant at TeraCyte, Primordium Labs, Spatial Genomics, and Asymptote Genetic Medicines. J.H.H. is an inventor on patents and patent applications related to ex utero embryogenesis, and a co-founder and chief scientific advisor of Renewal Bio, which has licensed the latter technologies.

M、 B.E.是TeraCyte、Primordium Labs、Spatial Genomics和渐近线遗传药物的联合创始人、科学顾问委员会成员或顾问。J、 H.H.是与子宫外胚胎发生有关的专利和专利申请的发明人，也是Renewal Bio的联合创始人和首席科学顾问，Renewal Bio已授权后者的技术。

The other authors declare no competing interests..

其他作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature thanks Manu Setty and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Nature感谢Manu Setty和另一位匿名审稿人为这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 A single-embryo, single cell atlas of mouse gastrulation.a, Bright-field images of all embryos from E5.5-E8.5 used to construct the ExE-Embryo atlas (Nembryos = 251) ordered by their morphological rank, annotated by their dissected age (top, E#) and morphological stage (TS#; Theiler stages, bottom).

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1小鼠原肠胚形成的单胚胎，单细胞图谱。A，来自E5.5-E8.5的所有胚胎的明场图像，用于构建ExE胚胎图谱（Nembryos=251），按其形态等级排序，由其解剖年龄（顶部，E#）和形态阶段（TS#；Theiler阶段，底部）注释。

Scale bar 100 µm. b, Bright-field images of two batches of flushed E4.5 blastocysts used for differential expression (Fig. 1g). Data represents 11 biologically independent samples over two experiments. Scale bar 100 µm. c, Embryonic (left) and ExE (right) cell count per embryo over each embryo’s transcriptional rank (p < 0.001, Wilcoxon rank test).

比例尺100微米。b、用于差异表达的两批冲洗的E4.5胚泡的明场图像（图1g）。数据代表两个实验中的11个生物学独立样本。比例尺100微米。c、胚胎（左）和ExE（右）细胞计数超过每个胚胎的转录等级（p<0.001，Wilcoxon等级检验）。

d, Metacell gene-gene expression (log2 absolute expression) of Col4a1 over Rhox5 showing transcriptional separation of ExE from embryonic and extraembryonic endoderm cell states. e, Embryo-embryo transcriptional similarity matrix, embryos are annotated based on embryonic age groups (see legend below, same as in Fig.

d、 Col4a1在Rhox5上的Metacell基因表达（log2绝对表达），显示ExE与胚胎和胚外内胚层细胞状态的转录分离。e、胚胎-胚胎转录相似性矩阵，胚胎基于胚胎年龄组进行注释（见下面的图例，与图1相同）。

1c). f, Developmental time (Et, left) and morphological rank (right) over embryo rank, annotated by age group.Source DataExtended Data Fig. 2 A unified extraembryonic/embryonic time-resolved model for gastrulation.a, Embryonic network flow model of differentiation (left). The model consists of metacells (nodes in rows, corresponding to the 16 embryonic age groups in Fig.

1c）。f、发育时间（Et，左）和形态等级（右）超过胚胎等级，由年龄组注释。源数据扩展数据图2原肠胚形成的统一胚外/胚胎时间分辨模型。A，分化的胚胎网络流模型（左）。该模型由元细胞（行中的节点，对应于图1中的16个胚胎年龄组）组成。

1c) distributed over Et (x axis), and flows (edges) linking metacells between adjacent age groups. The first time point represents an artificial common source for all metacells. Right, Marker heatmap of relative expression (log2 scale, negative v.

1c）分布在Et（x轴）上，流动（边缘）连接相邻年龄组之间的元细胞。第一个时间点代表所有元细胞的人工共同来源。右，相对表达的标记热图（log2标度，负v。

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Reprints and permissionsAbout this articleCite this articleHadas, R., Rubinstein, H., Mittnenzweig, M. et al. Temporal BMP4 effects on mouse embryonic and extraembryonic development.

转载和许可本文引用本文Hadas，R.，Rubinstein，H.，Mittnenzweig，M。等人。时间BMP4对小鼠胚胎和胚外发育的影响。

Nature (2024). https://doi.org/10.1038/s41586-024-07937-5Download citationReceived: 12 July 2022Accepted: 09 August 2024Published: 18 September 2024DOI: https://doi.org/10.1038/s41586-024-07937-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《自然》（2024）。https://doi.org/10.1038/s41586-024-07937-5Download引文收到日期：2022年7月12日接受日期：2024年8月9日发布日期：2024年9月18日OI：https://doi.org/10.1038/s41586-024-07937-5Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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