Tbx3 Controls Dppa3 Levels and Exit from Pluripotency toward Mesoderm.
Tbx3 Controls Dppa3 Levels and Exit from Pluripotency toward Mesoderm.
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DOI：
10.1016/j.stemcr.2015.05.009
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发表时间：
2015-07-14
影响因子：
5.9
通讯作者：
Lemischka IR
中科院分区：
文献类型：
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作者：
Waghray A;Saiz N;Jayaprakash AD;Freire AG;Papatsenko D;Pereira CF;Lee DF;Brosh R;Chang B;Darr H;Gingold J;Kelley K;Schaniel C;Hadjantonakis AK;Lemischka IR
Tbx3是T - box家族的成员，在发育、干细胞、细胞核重编程以及癌症中发挥重要作用。Tbx3缺失会诱导小鼠胚胎干细胞（mESCs）分化。然而，我们发现，在没有Tbx3的情况下，mESCs存在一种可替代的稳定多能性状态。对这种mESC状态的深入转录组分析表明，Dppa3是Tbx3的直接下游靶点。此外，Tbx3通过直接抑制分化所需的Wnt通路成员，促进细胞命运从多能细胞向内胚层祖细胞转变。Wnt信号调节mESCs向内胚层祖细胞的分化，并有助于维持原始多能性状态。我们发现，Wnt信号的下游靶点Tbx3精细调节Wnt信号在mESCs中的这些不同作用。总之，我们确定了一个信号 - 转录因子轴，它控制mESCs从自我更新的多能性状态向内胚层分化的转变。
Tbx3基因敲除的mESCs存在一种可替代的稳定多能性状态
Tbx3维持mESCs中Dppa3的稳态水平
Tbx3直接抑制像T（此处可能有遗漏信息）这样的内胚层特化基因
Tbx3抑制内胚层分化所需的Wnt通路基因
在本文中，莱米施卡及其同事表明，Tbx3控制mESCs从多能性向Wnt介导的内胚层分化的转变。他们描述了Tbx3基因敲除的mESCs的产生，并确定Dppa3是Tbx3在mESCs中的直接下游靶点。
Tbx3, a member of the T-box family, plays important roles in development, stem cells, nuclear reprogramming, and cancer. Loss of Tbx3 induces differentiation in mouse embryonic stem cells (mESCs). However, we show that mESCs exist in an alternate stable pluripotent state in the absence of Tbx3. In-depth transcriptome analysis of this mESC state reveals Dppa3 as a direct downstream target of Tbx3. Also, Tbx3 facilitates the cell fate transition from pluripotent cells to mesoderm progenitors by directly repressing Wnt pathway members required for differentiation. Wnt signaling regulates differentiation of mESCs into mesoderm progenitors and helps to maintain a naive pluripotent state. We show that Tbx3, a downstream target of Wnt signaling, fine tunes these divergent roles of Wnt signaling in mESCs. In conclusion, we identify a signaling-TF axis that controls the exit of mESCs from a self-renewing pluripotent state toward mesoderm differentiation. An alternate and stable pluripotent state of Tbx3 knockout mESCs exists Tbx3 maintains steady-state levels of Dppa3 in mESCs Tbx3 directly represses mesoderm specification genes like T Tbx3 represses Wnt pathway genes required for mesoderm differentiation In this article, Lemischka and colleagues show that Tbx3 controls the exit of mESCs from pluripotency toward Wnt-mediated mesoderm differentiation. They describe the generation of Tbx3 knockout mESCs and identify Dppa3 as a direct downstream target of Tbx3 in mESCs.