Yamamoto Hanako, Kurachi Masashi, Naruse Masae, Shibasaki Koji, Ishizaki Yasuki
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Biochem Biophys Res Commun. 2018 Feb 5;496(2):588-593. doi: 10.1016/j.bbrc.2018.01.090. Epub 2018 Jan 19.
We previously reported that BMP4 does not promote proliferation or differentiation of CD44-positive astrocyte precursor cells (APCs) but greatly promotes their survival in the presence of fibroblast growth factor-2 (FGF-2). In this study, we examined if BMP4 acts as a survival factor also for neural stem/progenitor cells (NPCs) isolated from ganglionic eminence of neonatal mouse brain. We found BMP4 promotes survival but not proliferation or differentiation of these cells, just as in the case for CD44-positive APCs. Microarray analysis revealed some candidate molecules in the signaling pathway downstream of BMP4. Among them, we focused on Id1 (inhibitor of DNA-binding 1) and Bcl-xL in this study. Expression of both genes was promoted in the presence of BMP4, and this promotion was reduced by dorsomorphin, an inhibitor of BMP4 signaling. Furthermore, cytochrome c release from mitochondria was significantly reduced in the presence of BMP4, suggesting up-regulation of Bcl-xL activity by BMP4. Id1 siRNA reduced the expression of Bcl-xL, and negated survival promoting effect of BMP4. These data suggest that BMP4 promotes survival of NPCs by enhancing the anti-apoptotic function of Bcl-xL via BMP4-Smad1/5/8-Id1 signaling.
我们之前报道过，骨形态发生蛋白4（BMP4）不会促进CD44阳性星形胶质细胞前体细胞（APC）的增殖或分化，但在成纤维细胞生长因子2（FGF-2）存在的情况下能极大地促进其存活。在本研究中，我们检测了BMP4对于从小鼠新生脑的神经节隆起分离出的神经干/祖细胞（NPC）是否也作为一种存活因子发挥作用。我们发现BMP4促进这些细胞的存活，但不促进其增殖或分化，就如同对CD44阳性APC的作用一样。微阵列分析揭示了BMP4下游信号通路中的一些候选分子。其中，在本研究中我们聚焦于DNA结合抑制因子1（Id1）和Bcl-xL。在BMP4存在的情况下，这两个基因的表达均被促进，并且这种促进作用被BMP4信号通路抑制剂 dorsomorphin所减弱。此外，在BMP4存在的情况下，线粒体细胞色素c的释放显著减少，提示BMP4上调了Bcl-xL的活性。Id1小干扰RNA（siRNA）降低了Bcl-xL的表达，并消除了BMP4的存活促进作用。这些数据表明，BMP4通过BMP4-Smad1/5/8-Id1信号通路增强Bcl-xL的抗凋亡功能，从而促进NPC的存活。
