Lamba Adiyant, Zhu Meng, Meglicki Maciej, Czukiewska Sylwia, Balasubramaniam Lakshmi, Hadas Ron, Weishaupt Nina, Patel Ekta M, Kavanagh Yu Hua, Wang Ran, Jing Naihe, Zernicka-Goetz Magdalena
Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
bioRxiv. 2025 Jun 23:2024.07.26.605266. doi: 10.1101/2024.07.26.605266.
The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry breaking event is executed through polarization of cells at the 8-cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8-cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8-cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4-cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4-cell stage and polarization at the 8-cell stage, mechanisms of the first lineage allocation that had been considered separate.
小鼠和人类胚胎中的首次谱系分配将内细胞团（ICM）与外层滋养外胚层（TE）区分开来。这种对称性破缺事件是通过8细胞阶段细胞的极化以及随后的不对称分裂来实现的，从而产生极性（TE）细胞和非极性（ICM）细胞。在此，我们表明胚胎极化意外地是异步的。在8细胞阶段早期和晚期极化的细胞具有不同的分子和形态特性，这些特性指导它们后续的谱系特化，早期极化的细胞倾向于产生TE谱系。最近的研究也表明，在首次谱系分配中，8细胞阶段之前细胞之间的异质性也起作用：在4细胞阶段甲基转移酶CARM1活性降低的细胞易向TE命运发展。在此，我们证明CARM1活性降低及其底物BAF155的上调促进早期极化和TE特化。这些发现揭示了4细胞阶段的不对称性与8细胞阶段的极化之间的联系，而这两个首次谱系分配机制此前一直被认为是相互独立的。
