Generative model for the first cell fate bifurcation in mammalian development.

IF 3.6 2区生物学 Q1 DEVELOPMENTAL BIOLOGY

Development Pub Date : 2025-09-01 Epub Date: 2025-09-05 DOI:10.1242/dev.204717

Maria Avdeeva, Madeleine Chalifoux, Bradley Joyce, Stanislav Y Shvartsman, Eszter Posfai

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Abstract

The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live-imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, which are key transcription factors of the TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.

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哺乳动物发育中第一次细胞命运分叉的生成模型。

哺乳动物发育中的第一次细胞命运分化将细胞导向着床前胚胎的滋养外胚层（TE）或内细胞团（ICM）室。这一决定是由转录共激活因子YAP的亚细胞定位调控的，并在几个逐步异步的切割分裂中发生。由于卵裂球的这种非同步和可变排列，从固定胚胎中重建TE/ICM细胞规格的动力学是极具挑战性的。为了解决这个问题，我们开发了一种实时成像方法，并应用它分别测量核YAP及其直接靶基因CDX2和SOX2的成对动态，CDX2和SOX2是TE和ICM的关键转录因子。利用这些数据集，我们构建了第一细胞命运分岔的生成模型，该模型揭示了TE和ICM细胞分配的时间依赖性统计。除了对整个YAP/CDX2/SOX2基序的联合动力学进行可测试的预测外，该模型还揭示了关键细胞命运决定因素诱导时间的随机性，并确定了这种诱导所必需或充分的YAP动力学特征。值得注意的是，SOX2在ICM细胞中表达的时间异质性尤为突出。由于ICM内的异质性与胚胎中第二个细胞命运决定的开始有关，因此了解这种可变性的起源具有关键意义。提出的方法揭示了第一个细胞命运选择的动力学，并为解剖小鼠发育中的下一个细胞命运决定奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Development 生物-发育生物学

CiteScore

6.70

自引率

4.30%

发文量

433

审稿时长

3 months

期刊介绍： Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community. Development includes a Techniques and Resources section for the publication of new methods, datasets, and other types of resources. Papers describing new techniques should include a proof-of-principle demonstration that the technique is valuable to the developmental biology community; they need not include in-depth follow-up analysis. The technique must be described in sufficient detail to be easily replicated by other investigators. Development will also consider protocol-type papers of exceptional interest to the community. We welcome submission of Resource papers, for example those reporting new databases, systems-level datasets, or genetic resources of major value to the developmental biology community. For all papers, the data or resource described must be made available to the community with minimal restrictions upon publication. To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.