Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development.
Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development.
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DOI：
10.1016/j.celrep.2015.06.060
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发表时间：
2015-07-28
期刊：
影响因子：
8.8
通讯作者：
Fisher AG
中科院分区：
文献类型：
--
作者：
Landeira D;Bagci H;Malinowski AR;Brown KE;Soza-Ried J;Feytout A;Webster Z;Ndjetehe E;Cantone I;Asenjo HG;Brockdorff N;Carroll T;Merkenschlager M;Fisher AG
Jarid 2是Polycomb Repressor complex 2（PRC 2）的一部分，负责全基因组H3 K27 me 3沉积。然而，与其他PRC 2缺陷型胚胎干细胞（ESC）不同，Jarid 2缺陷型ESC表现出严重的分化阻滞、改变的集落形态和独特的基因表达失调模式。在这里，我们发现Jarid 2 −/− ESCs组成性地表达高水平的Nanog，但减少了PCP信号组分Wnt 9a，Prickle 1和Fzd 2，并降低了β-catenin活性。从野生型ESC中去除Wnt 9a/Prickle 1/Fzd 2或过表达Nanog在很大程度上表型复制了这些细胞缺陷。Jarid 2 −/−与野生型ESC的共培养恢复了不同的Nanog表达和β-catenin活性，并可以部分挽救突变细胞的分化阻滞。此外，我们发现，缺乏Jarid 2或Wnt 9a/Prickle 1/Fzd 2或过表达Nanog的ESC在注射到正常E3.5囊胚中时诱导多个ICM形成。这些数据描述了Jarid 2在调节核心多能性和Wnt/PCP信号通路中的先前未被认识的作用，该通路对于ESC分化和植入前发育是重要的。缺乏Jarid 2的ESC显示组成型Nanog表达缺乏Jarid 2的ESC具有降低的PCP/Wnt信号传导。Jarid 2-null和WT ESC的共培养恢复了分化能力，Jarid 2-null ESC在注射到E3.5小鼠胚泡后形成多于一个ICM。显示Jarid 2缺失ESC具有降低的Wnt 9a/Prickle 1/Fzd 2和低的β-连环蛋白活性，导致改变的粘附、Nanog的组成型表达和分化失败。他们的实验确定了Jarid 2在调节ESC自我更新和分化之间的平衡方面的非经典功能。
Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2−/− ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2−/− with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development. ESCs lacking Jarid2 show constitutive Nanog expression ESCs lacking Jarid2 have reduced PCP/Wnt signaling Co-culture of Jarid2-null and WT ESCs restores differentiation capability Jarid2-null ESCs form more than one ICM upon injection to E3.5 mouse blastocysts Landeira et al. show that Jarid2-null ESCs have reduced Wnt9a/Prickle1/Fzd2 and low β-catenin activity, resulting in altered adhesion, constitutive expression of Nanog, and failure to differentiate. Their experiments identify a non-canonical function for Jarid2 in regulating the balance between ESC self-renewal and differentiation.