CXXC5 Is a Novel BMP4-regulated Modulator of Wnt Signaling in Neural Stem Cells
CXXC5 Is a Novel BMP4-regulated Modulator of Wnt Signaling in Neural Stem Cells
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DOI：
10.1074/jbc.m808119200
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发表时间：
2009-02-06
影响因子：
4.8
通讯作者：
Hermanson, Ola
中科院分区：
文献类型：
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作者：
Andersson, Therese;Soedersten, Erik;Hermanson, Ola
骨形态发生蛋白如BMP 4对于端脑前脑结构的正常发育是必不可少的，并诱导端脑神经干细胞分化成各种细胞命运，包括星形胶质细胞、神经元和间充质细胞。关于祖细胞对BMP 4反应的时空差异的机制还知之甚少。在一项旨在鉴定端脑神经干细胞中BMP 4信号转导新靶点的筛选中，我们发现以前未表征的因子CXXC5的mRNA水平在BMP 4刺激后可重复上调。在体内，CXXC5的表达重叠与BMP 4相邻的Wnt3a的表达在端脑的背侧区域，包括发展脉络丛。CXXC5显示与Shakespex的部分同源性，Shakespex是一种先前显示与Wnt信号传导中间体Dishevelled（Dvl）相互作用的相关蛋白。事实上，CXXC5和Dvl共定位于细胞质中，并在免疫共沉淀实验中相互作用。此外，荧光共振能量转移（FRET）实验证实CXXC5和Dvl2在神经干细胞中位于紧密的空间接近。对CXXC5功能作用的研究表明，CXXC5的过表达或暴露于BMP 4抑制了经典Wnt信号转导靶点Axin2的水平，CXXC5减弱了Wnt3a介导的TOP flash报告基因活性的增加。因此，CXXC5的RNA干扰减弱了BMP 4介导的Axin2水平的降低，并促进了神经干细胞对Wnt3a的反应。我们认为CXXC5是神经干细胞中BMP 4诱导的Wnt信号抑制剂。
Bone morphogenetic proteins such as BMP4 are essential for proper development of telencephalic forebrain structures and induce differentiation of telencephalic neural stem cells into a variety of cellular fates, including astrocytic, neuronal, and mesenchymal cells. Little is yet understood regarding the mechanisms that underlie the spatiotemporal differences in progenitor response to BMP4. In a screen designed to identify novel targets of BMP4 signaling in telencephalic neural stem cells, we found the mRNA levels of the previously uncharacterized factor CXXC5 reproducibly up-regulated upon BMP4 stimulation. In vivo, CXXC5 expression overlapped with BMP4 adjacent to Wnt3a expression in the dorsal regions of the telencephalon, including the developing choroid plexus. CXXC5 showed partial homology with Idax, a related protein previously shown to interact with the Wnt-signaling intermediate Dishevelled (Dvl). Indeed CXXC5 and Dvl co-localized in the cytoplasm and interacted in co-immunoprecipitation experiments. Moreover, fluorescence resonance energy transfer (FRET) experiments verified that CXXC5 and Dvl2 were located in close spatial proximity in neural stem cells. Studies of the functional role of CXXC5 revealed that overexpression of CXXC5 or exposure to BMP4 repressed the levels of the canonical Wnt signaling target Axin2, and CXXC5 attenuated Wnt3a-mediated increase in TOPflash reporter activity. Accordingly, RNA interference of CXXC5 attenuated the BMP4-mediated decrease in Axin2 levels and facilitated the response to Wnt3a in neural stem cells. We propose that CXXC5 is acting as a BMP4-induced inhibitor of Wnt signaling in neural stem cells.