Geiselmann Anna, Micouin Adèle, Vandormael-Pournin Sandrine, Laville Vincent, Chervova Almira, Mella Sébastien, Navarro Pablo, Cohen-Tannoudji Michel
Institut Pasteur, Université Paris Cité, CNRS UMR 3738, Epigenomics, Proliferation, and the Identity of Cells, Department of Developmental and Stem Cell Biology, 75015 Paris, France; Sorbonne Université, Complexité du Vivant, 75005 Paris, France; Institut Pasteur, Université Paris Cité, CNRS UMR3738, Early Mammalian Development and Stem Cell Biology, 75015 Paris, France.
Institut Pasteur, Université Paris Cité, CNRS UMR 3738, Epigenomics, Proliferation, and the Identity of Cells, Department of Developmental and Stem Cell Biology, 75015 Paris, France; Institut Pasteur, Université Paris Cité, CNRS UMR3738, Early Mammalian Development and Stem Cell Biology, 75015 Paris, France; Université Paris Cité, BioSPC, 75013 Paris, France.
Dev Cell. 2025 Jan 20;60(2):204-219.e6. doi: 10.1016/j.devcel.2024.10.001. Epub 2024 Oct 25.
The inner cell mass (ICM) of early mouse embryos is specified into epiblast (Epi) and primitive endoderm (PrE) lineages during blastocyst formation. The antagonistic transcription factors (TFs) NANOG and GATA-binding protein 6 (GATA6) in combination with fibroblast growth factor (FGF)/extracellular-signal-regulated kinase (ERK) signaling are central actors in ICM fate choice. However, what initiates the specification of ICM progenitors into Epi or PrE and whether other factors are involved in this process has not been fully understood yet. Here, we show that phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) is constitutively active during preimplantation development. Using pharmacological inhibition, we demonstrate that PI3K/AKT enables the formation of a functional ICM capable of giving rise to both the Epi and the PrE: it maintains the expression of the TF NANOG, which specifies the Epi, and confers responsiveness to FGF4, which is essential for PrE specification. Our work thus identifies PI3K/AKT signaling as an upstream regulator controlling the molecular events required for both Epi and PrE specification.
在囊胚形成过程中，早期小鼠胚胎的内细胞团（ICM）被指定分化为上胚层（Epi）和原始内胚层（PrE）谱系。拮抗转录因子（TFs）NANOG和GATA结合蛋白6（GATA6）与成纤维细胞生长因子（FGF）/细胞外信号调节激酶（ERK）信号通路共同作用，是ICM命运选择的核心因素。然而，是什么启动了ICM祖细胞向Epi或PrE的分化，以及该过程是否涉及其他因素，目前尚未完全明确。在此，我们发现磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）在植入前发育过程中持续处于激活状态。通过药理学抑制，我们证明PI3K/AKT能够促使形成一个有功能的ICM，该ICM能够分化产生Epi和PrE：它维持TF NANOG的表达，NANOG决定了Epi的分化方向，并且赋予细胞对FGF4的反应性，FGF4对PrE的分化至关重要。因此，我们的研究确定PI3K/AKT信号通路是一种上游调节因子，控制着Epi和PrE分化所需的分子事件。
