The Zinc Finger Transcription Factor Ovol2 Acts Downstream of the Bone Morphogenetic Protein Pathway to Regulate the Cell Fate Decision between Neuroectoderm and Mesendoderm*
The Zinc Finger Transcription Factor Ovol2 Acts Downstream of the Bone Morphogenetic Protein Pathway to Regulate the Cell Fate Decision between Neuroectoderm and Mesendoderm*
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DOI：
10.1074/jbc.m112.418376
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发表时间：
2013-01
期刊：
影响因子：
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通讯作者：
Ting Zhang;Qingqing Zhu;Zhihui Xie;Yongfeng Chen;Yunbo Qiao;Lingyu Li;N. Jing
中科院分区：
文献类型：
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作者：
Ting Zhang;Qingqing Zhu;Zhihui Xie;Yongfeng Chen;Yunbo Qiao;Lingyu Li;N. Jing
背景：BMP信号通过下游转录因子促进中内胚层分化并抑制神经分化。结果：Ovol 2被BMP 4上调，并且其敲低损害了BMP在神经外胚层/中内胚层细胞命运决定中的功能。结论：Ovol 2作为BMP下游靶点，抑制神经分化，促进中内胚层分化。意义：本研究揭示了BMP信号如何调控早期细胞命运决定的机制。在早期胚胎发育过程中，骨形态发生蛋白（BMP）信号传导对于神经/非神经细胞命运决定至关重要。BMP信号传导抑制早熟神经分化并允许中胚层、内胚层和表皮的适当分化。然而，BMP途径介导的细胞命运决定的机制仍然很大程度上未知。在这里，我们表明，Ovol 2，它编码一个进化上保守的锌指转录因子的表达，在小鼠胚胎干细胞的神经分化过程中下调。在胚胎干细胞中敲低Ovol 2促进神经转化并抑制中内胚层分化，而Ovol 2过表达引起相反的表型。此外，Ovol 2敲低部分挽救了BMP 4的神经抑制和中内胚层诱导。机制研究进一步表明，BMP 4通过Smad 1/5/8与Ovol 2基因的第二个内含子结合来直接调节Ovol 2的表达。在鸡胚中，cOvol 2的表达被特异性地排除在神经区域之外，并被BMP 4上调。此外，cOvol 2在预期神经板中的异位表达抑制了确定性神经板标记物cSox 2的表达。总之，这些结果表明，Ovol 2在神经外胚层和中内胚层之间的细胞命运决定中在BMP途径的下游起作用，以确保适当的胚层发育。
Background: BMP signaling promotes mesendoderm differentiation and inhibits neural differentiation through downstream transcription factors. Results: Ovol2 is up-regulated by BMP4, and its knockdown impairs BMP function in the neuroectodermal/mesendodermal cell fate decision. Conclusion: Ovol2 acts as a novel BMP downstream target to inhibit neural differentiation and promote mesendodermal differentiation. Significance: This study uncovers the mechanism of how BMP signaling regulates early cell fate decision. During early embryonic development, bone morphogenetic protein (BMP) signaling is essential for neural/non-neural cell fate decisions. BMP signaling inhibits precocious neural differentiation and allows for proper differentiation of mesoderm, endoderm, and epidermis. However, the mechanisms underlying the BMP pathway-mediated cell fate decision remain largely unknown. Here, we show that the expression of Ovol2, which encodes an evolutionarily conserved zinc finger transcription factor, is down-regulated during neural differentiation of mouse embryonic stem cells. Knockdown of Ovol2 in embryonic stem cells facilitates neural conversion and inhibits mesendodermal differentiation, whereas Ovol2 overexpression gives rise to the opposite phenotype. Moreover, Ovol2 knockdown partially rescues the neural inhibition and mesendodermal induction by BMP4. Mechanistic studies further show that BMP4 directly regulates Ovol2 expression through the binding of Smad1/5/8 to the second intron of the Ovol2 gene. In the chick embryo, cOvol2 expression is specifically excluded from neural territory and is up-regulated by BMP4. In addition, ectopic expression of cOvol2 in the prospective neural plate represses the expression of the definitive neural plate marker cSox2. Taken together, these results indicate that Ovol2 acts downstream of the BMP pathway in the cell fate decision between neuroectoderm and mesendoderm to ensure proper germ layer development.