近日，国际学术期刊Journal of Biological Chemistry发表了上海生科院生化与细胞所景乃禾研究组题为“The Zinc-Finger Transcription Factor Ovol2 Acts Downstream of the BMP Pathway to Regulate the Cell Fate Decision between Neuroectoderm and Mesendoderm”的最新研究成果，该研究发现锌指蛋白转录因子Ovol2作为一个新的BMP信号下游靶基因，参与调控神经外胚层和中内胚层间的命运决定。
在高等动物的早期胚胎发育过程中，BMP信号通路在神经/非神经的细胞命运决定中发挥了极其重要的作用。BMP信号抑制神经命运的提前发生，保证了中、内胚层和表皮的正常发育。然而BMP信号调控神经外胚层和中内胚层间命运决定的分子机制仍然不甚清楚。
景乃禾研究组博士研究生张婷等发现在小鼠胚胎干细胞（Embryonic Stem Cells，ESCs）的神经分化过程中，锌指蛋白转录因子Ovol2的表达水平持续下降。功能研究发现，Ovol2能够抑制ESCs的神经分化，并促进其向中内胚层细胞分化。此外，通过shRNA抑制Ovol2的表达，能显著削弱BMP信号对神经分化的抑制和对中内胚层分化的促进作用。机制研究进一步发现，BMP信号通过磷酸化的Smad1/5/8结合到Ovol2基因的第二个内含子上直接上调其表达。在早期鸡胚中，Ovol2表达于神经区域之外，并被BMP4上调。而在早期鸡胚的未来神经板区域过表达Ovol2，能够明显抑制神经板标记基因Sox2的表达。这一工作揭示了BMP信号在早期胚胎发育中，如何通过其下游的转录因子，调控神经外胚层和中内胚层的命运决定，从而保障各胚层发育的正常进行。
该项工作得到了国家科技部、国家自然科学基金委、中国科学院及上海市科委的经费支持。（生物谷Bioon.com）
doi:10.1074/jbc.M112.418376
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The Zinc-Finger Transcription Factor Ovol2 Acts Downstream of the BMP Pathway to Regulate the Cell Fate Decision between Neuroectoderm and Mesendoderm
Ting Zhang, Qingqing Zhu, Zhihui Xie, Yongfeng Chen, Yunbo Qiao, Lingyu Li and Naihe Jing*
During early embryonic development, 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 downregulated during neural differentiation of mouse embryonic stem cells (ESCs). Knockdown of Ovol2 in ESCs 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 upregulated 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.
