The Hippo Pathway Member Nf2 Is Required for Inner Cell Mass Specification
The Hippo Pathway Member Nf2 Is Required for Inner Cell Mass Specification
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DOI：
10.1016/j.cub.2013.05.044
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发表时间：
2013-07-08
期刊：
影响因子：
9.2
通讯作者：
Rossant, Janet
中科院分区：
文献类型：
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作者：
Cockburn, Katie;Biechele, Steffen;Rossant, Janet
在哺乳动物的发育过程中，最先确定的两个谱系是滋养外胚层（TE）和内细胞团（ICM）。Hippo途径激酶Lats 1和2（Lats 1/2）和转录共激活因子雅普在该特化过程中发挥重要作用[1]。在胚胎的外部细胞中，雅普位于细胞核内，并与Tead 4合作诱导TE特异性转录因子Cdx 2。在细胞内，Lats 1/2磷酸化雅普并阻止其核定位。在这种情况下，作用于Lats 1/2和雅普上游的因素尚未确定。在这里，我们证明了上游海马通路成员Nf 2/梅林所需的Lats 1/2依赖的雅普磷酸化在植入前胚胎。注射显性负性Nf 2 mRNA导致雅普错误定位和异位Cdx 2表达，这种效应可以通过Lats 2激酶的过表达来挽救。合子Nf 2突变体囊胚在雅普定位和Cdx 2表达方面有轻度缺陷，但在去除母体和合子Nf 2后，这些缺陷变得更加严重。母合子突变体的内细胞不能建立多能性ICM并形成过量的TE，导致笔植入致死。总之，这些数据建立了一个明确的作用Nf 2上游的雅普在植入前胚胎，并证明海马信号是必不可少的隔离ICM从TE。
During mammalian development, the first two lineages to be specified are the trophectoderm (TE) and the inner cell mass (ICM). The Hippo pathway kinases Lats 1 and 2 (Lats1/2) and the transcriptional coactivator Yap play important roles in this specification process [1]. In outside cells of the embryo, Yap is nuclear localized and cooperates with Tead4 to induce the TE-specifying transcription factor Cdx2. In inside cells, Lats1/2 phosphorylate Yap and prevent its nuclear localization. The factors acting upstream of Lats1/2 and Yap in this context have not been identified. Here, we demonstrate that the upstream Hippo pathway member Nf2/Merlin is required for Lats1/2-dependent Yap phosphorylation in the preimplantation embryo. Injection of dominant-negative Nf2 mRNA causes Yap mislocalization and ectopic Cdx2 expression, effects that can be rescued by overexpression of Lats2 kinase. Zygotic Nf2 mutant blastocysts have mild defects in Yap localization and Cdx2 expression, but these become much more severe upon removal of both maternal and zygotic Nf2. The inside cells of maternal-zygotic mutants fail to establish a pluripotent ICM and form excess TE, resulting in pen-implantation lethality. Together, these data establish a clear role for Nf2 upstream of Yap in the preimplantation embryo and demonstrate that Hippo signaling is essential to segregate the ICM from the TE.