8月31日,，《生物化學(xué)期刊》（The Journal of Biological Chemistry）在線發(fā)表了中科院上海生命科學(xué)研究院生化與細(xì)胞所李林研究組的最新研究成果，揭示了NFAT蛋白調(diào)控經(jīng)典Wnt信號(hào)通路的分子機(jī)制，及其在神經(jīng)祖細(xì)胞增殖和分化過(guò)程中的功能,。
Wnt信號(hào)通路是廣泛存在于多細(xì)胞真核生物中的一條高度保守的信號(hào)通路,，在胚胎發(fā)育過(guò)程中起到重要作用,，例如促進(jìn)神經(jīng)祖細(xì)胞的增殖,，抑制其分化。在對(duì)Wnt信號(hào)通路的研究中,，其他信號(hào)通路與Wnt信號(hào)通路之間的相互作用也成為近年來(lái)研究的熱點(diǎn),。
博士研究生黃濤等人發(fā)現(xiàn)，NFAT這一鈣信號(hào)的重要下游分子在鈣信號(hào)的調(diào)節(jié)下，與Dvl這一經(jīng)典Wnt信號(hào)通路的重要分子存在相互作用,。在細(xì)胞核內(nèi),，NFAT通過(guò)與Dvl的相互作用，抑制Dvl與β-catenin的相互作用,，從而影響轉(zhuǎn)錄復(fù)合物（Dvl-β-catenin-TCF-c-Jun）的形成,，進(jìn)而起到抑制經(jīng)典Wnt信號(hào)通路的作用。進(jìn)一步的工作還發(fā)現(xiàn),，在雞胚神經(jīng)管發(fā)育的過(guò)程中,，NFAT通過(guò)對(duì)經(jīng)典Wnt信號(hào)的抑制，從而抑制神經(jīng)祖細(xì)胞的增殖,，促進(jìn)神經(jīng)細(xì)胞的分化,。
該研究首次詳細(xì)闡明了NFAT對(duì)經(jīng)典Wnt信號(hào)產(chǎn)生抑制的分子機(jī)制，并揭示了NFAT在神經(jīng)祖細(xì)胞分化過(guò)程中的重要作用,。
該項(xiàng)工作與景乃禾研究組合作完成,，并得到了科技部,、國(guó)家自然科學(xué)基金委,、中國(guó)科學(xué)院以及上海市科委的經(jīng)費(fèi)支持。(生物谷 Bioon.com)
doi:10.1074/jbc.P111.253401
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NFAT proteins repress canonical Wnt signaling via its interaction with Dvl and participate in regulating neural progenitor cell proliferation and differentiation
Tao Huang, Zhihui Xie, Jiyong Wang, Meng Li, Naihe Jing and Lin Li
The Ca2+ signaling pathway appears to regulate the processes of the early development through its antagonism of canonical Wnt/β-catenin signaling pathway. However, the underlying mechanism is still poorly understood. Here, we show that NFAT, a component of Ca2+ signaling, directly interacts with Dvl in a Ca2+-dependent manner. A dominant-negative form of NFAT rescued the inhibition of the Wnt/β-catenin pathway triggered by Ca2+ signal. NFAT functioned downstream of β-catenin without interfering with its stability, but influencing the interaction of β-catenin with Dvl by its competitively binding to Dvl. Furthermore, we demonstrate that NFAT is a regulator in the proliferation and differentiation of neural progenitor cells by modulating canonical Wnt/β-catenin signaling pathway in the neural tube of chick embryo. Our findings suggest that NFAT negatively regulates canonical Wnt/β-catenin signaling by binding to Dvl, thereby participating in vertebrate neurogenesis.
