Avdeeva Maria, Chalifoux Madeleine, Joyce Bradley, Shvartsman Stanislav Y, Posfai Eszter
Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
Development. 2025 Aug 5. doi: 10.1242/dev.204717.
The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in preimplantation 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, key transcription factors of 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.
哺乳动物发育过程中的首次细胞命运分化决定了植入前胚胎中的细胞是走向滋养外胚层（TE）还是内细胞团（ICM）。这一决定由转录共激活因子YAP的亚细胞定位调控，并在几个逐渐不同步的卵裂过程中发生。由于这种不同步以及卵裂球的可变排列，从固定胚胎重建TE/ICM细胞特化的动态过程极具挑战性。为了解决这个问题，我们开发了一种活体成像方法，并将其应用于测量核YAP及其直接靶基因CDX2和SOX2（分别是TE和ICM的关键转录因子）的成对动态变化。利用这些数据集，我们构建了首次细胞命运分化的生成模型，该模型揭示了TE和ICM细胞分配的时间依赖性统计规律。除了对完整的YAP/CDX2/SOX2基序的联合动态做出可测试的预测外，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YAP动态变化中对于这种诱导必要或充分的特征。值得注意的是，ICM细胞中SOX2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次细胞命运决定的启动有关，了解这种变异性的起源具有关键意义。所提出的方法揭示了首次细胞命运选择的动态过程，并为剖析小鼠发育过程中的下一次细胞命运决定奠定了基础。
