Par-aPKC-dependent and -independent mechanisms cooperatively control cell polarity, Hippo signaling, and cell positioning in 16-cell stage mouse embryos
Par-aPKC-dependent and -independent mechanisms cooperatively control cell polarity, Hippo signaling, and cell positioning in 16-cell stage mouse embryos
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DOI：
10.1111/dgd.12235
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发表时间：
2015-10-01
影响因子：
2.5
通讯作者：
Sasaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Hirate, Yoshikazu;Hirahara, Shino;Sasaki, Hiroshi
在植入前小鼠胚胎中，Hippo信号通路在调节滋养外胚层（TE）和内细胞团（ICM）的命运方面发挥着核心作用。在具有超过32个细胞的早期囊胚中，Par-aPKC系统控制外细胞沿着顶基底轴的极化，并且细胞极性抑制Hippo信号传导。Hippo信号转导的失活促进共激活蛋白雅普的核积累，导致TE特异性基因的诱导。然而，类似的机制是否在早期阶段起作用尚不得而知。在这里，我们发现在16细胞期胚胎中有略微不同的机制。与32细胞期胚胎相似，Par-aPKC系统的破坏激活了Hippo信号传导并抑制了外细胞中的核雅普和Cdx 2表达。然而，与32-细胞期胚胎不同，具有破坏的Par-aPKC系统的16-细胞期胚胎维持磷酸化Ezrin/Radixin/Moesin（p-ERM）的顶端定位，并且对雅普和Cdx 2的影响较弱。此外，正常的16细胞期胚胎通常在外部位置含有非极性细胞。在这些细胞中，Hippo通路被强烈激活，雅普被排除在细胞核之外，因此类似于内细胞。8-细胞期胚胎分裂球形成极性-非极性偶联体，其显示不同水平的核雅普，极性细胞吞噬非极性细胞。这些结果表明，在16-细胞阶段的细胞极化是由两个Par-aPKC依赖性和非依赖性机制。不对称细胞分裂参与细胞极性控制，细胞极性调节细胞定位，并很可能控制Hippo信号传导。
In preimplantation mouse embryos, the Hippo signaling pathway plays a central role in regulating the fates of the trophectoderm (TE) and the inner cell mass (ICM). In early blastocysts with more than 32 cells, the Par-aPKC system controls polarization of the outer cells along the apicobasal axis, and cell polarity suppresses Hippo signaling. Inactivation of Hippo signaling promotes nuclear accumulation of a coactivator protein, Yap, leading to induction of TE-specific genes. However, whether similar mechanisms operate at earlier stages is not known. Here, we show that slightly different mechanisms operate in 16-cell stage embryos. Similar to 32-cell stage embryos, disruption of the Par-aPKC system activated Hippo signaling and suppressed nuclear Yap and Cdx2 expression in the outer cells. However, unlike 32-cell stage embryos, 16-cell stage embryos with a disrupted Par-aPKC system maintained apical localization of phosphorylated Ezrin/Radixin/Moesin (p-ERM), and the effects on Yap and Cdx2 were weak. Furthermore, normal 16-cell stage embryos often contained apolar cells in the outer position. In these cells, the Hippo pathway was strongly activated and Yap was excluded from the nuclei, thus resembling inner cells. Dissociated blastomeres of 8-cell stage embryos form polar-apolar couplets, which exhibit different levels of nuclear Yap, and the polar cell engulfed the apolar cell. These results suggest that cell polarization at the 16-cell stage is regulated by both Par-aPKC-dependent and -independent mechanisms. Asymmetric cell division is involved in cell polarity control, and cell polarity regulates cell positioning and most likely controls Hippo signaling.