Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Cardiothoracic Surgery, Stanford University, California, USA.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Mol Cell Neurosci. 2020 Apr;104:103481. doi: 10.1016/j.mcn.2020.103481. Epub 2020 Mar 10.
The development of the cerebral cortex depends on numerous parameters, including extracellular cues and microenvironmental factors that also affect gene expression. C-Terminal Binding Proteins (CtBPs) 1 and 2 are transcriptional co-repressors which have been shown to be critically involved in embryonic development. CtBPs are oxygen sensing molecules, and we have previously demonstrated an important role for CtBP1 in integrating oxygen levels and BMP-signaling to influence neural progenitor fate choice. In turn, CtBP2 has been associated with neurodevelopment and neurological disease, and we have shown that CtBP2 acetylation and dimerization, required for proper transcriptional activity, are regulated by microenvironmental oxygen levels. Yet, the putative function of CtBP2 in mammalian cortical development and neurogenesis in vivo is still largely unknown. Here we show that CtBP2 was widely expressed by neural stem and progenitor cells (NSPCs) as well as neurons during cortical development in mice. By using in utero electroporation of siRNA to reduce the levels of CtBP2 mRNA and protein in the developing mouse brain, we found that the NSPC proliferation and migration were largely perturbed, while glial differentiation under these conditions remained unchanged. Our study provides evidence that CtBP2 is required for the maintenance and migration of the NSPCs during mouse cortical development.
大脑皮层的发育取决于许多参数，包括细胞外线索和微环境因素，这些因素也会影响基因表达。C 端结合蛋白（CtBP）1 和 2 是转录共抑制因子，它们被证明在胚胎发育中起着至关重要的作用。CtBPs 是氧感应分子，我们之前已经证明 CtBP1 在整合氧水平和 BMP 信号以影响神经祖细胞命运选择方面起着重要作用。相反，CtBP2 与神经发育和神经疾病有关，我们已经表明，CtBP2 的乙酰化和二聚化（这是适当转录活性所必需的）受到微环境氧水平的调节。然而，CtBP2 在哺乳动物皮质发育和体内神经发生中的假定功能在很大程度上仍然未知。在这里，我们发现在小鼠皮质发育过程中，CtBP2 广泛表达于神经干细胞和祖细胞（NSPCs）以及神经元中。通过在体电穿孔将 siRNA 转染到发育中的小鼠大脑中以降低 CtBP2 mRNA 和蛋白的水平，我们发现 NSPC 的增殖和迁移受到了很大的干扰，而在这些条件下神经胶质分化保持不变。我们的研究提供了证据，证明 CtBP2 对于维持和迁移 NSPCs 在小鼠皮质发育过程中是必需的。
