近日,，國際學(xué)術(shù)期刊Journal of Biological Chemistry發(fā)表了上海生科院生化與細(xì)胞所景乃禾研究組題為“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，該研究發(fā)現(xiàn)鋅指蛋白轉(zhuǎn)錄因子Ovol2作為一個新的BMP信號下游靶基因,，參與調(diào)控神經(jīng)外胚層和中內(nèi)胚層間的命運(yùn)決定,。
在高等動物的早期胚胎發(fā)育過程中,，BMP信號通路在神經(jīng)/非神經(jīng)的細(xì)胞命運(yùn)決定中發(fā)揮了極其重要的作用。BMP信號抑制神經(jīng)命運(yùn)的提前發(fā)生,，保證了中,、內(nèi)胚層和表皮的正常發(fā)育。然而BMP信號調(diào)控神經(jīng)外胚層和中內(nèi)胚層間命運(yùn)決定的分子機(jī)制仍然不甚清楚,。
景乃禾研究組博士研究生張婷等發(fā)現(xiàn)在小鼠胚胎干細(xì)胞（Embryonic Stem Cells,，ESCs）的神經(jīng)分化過程中，鋅指蛋白轉(zhuǎn)錄因子Ovol2的表達(dá)水平持續(xù)下降,。功能研究發(fā)現(xiàn),，Ovol2能夠抑制ESCs的神經(jīng)分化，并促進(jìn)其向中內(nèi)胚層細(xì)胞分化,。此外,，通過shRNA抑制Ovol2的表達(dá)，能顯著削弱BMP信號對神經(jīng)分化的抑制和對中內(nèi)胚層分化的促進(jìn)作用,。機(jī)制研究進(jìn)一步發(fā)現(xiàn),，BMP信號通過磷酸化的Smad1/5/8結(jié)合到Ovol2基因的第二個內(nèi)含子上直接上調(diào)其表達(dá)。在早期雞胚中,，Ovol2表達(dá)于神經(jīng)區(qū)域之外,，并被BMP4上調(diào),。而在早期雞胚的未來神經(jīng)板區(qū)域過表達(dá)Ovol2，能夠明顯抑制神經(jīng)板標(biāo)記基因Sox2的表達(dá),。這一工作揭示了BMP信號在早期胚胎發(fā)育中,，如何通過其下游的轉(zhuǎn)錄因子，調(diào)控神經(jīng)外胚層和中內(nèi)胚層的命運(yùn)決定,，從而保障各胚層發(fā)育的正常進(jìn)行,。
該項(xiàng)工作得到了國家科技部、國家自然科學(xué)基金委,、中國科學(xué)院及上海市科委的經(jīng)費(fèi)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.
