MicroRNA对大脑皮层神经发生的反馈环路调控机理

During the development of the cerebral cortex, abnormal proliferation and differentiation of neural stem cells and neural progenitors can lead to brain malformations and dysfunction, such as epilepsy, mental retardation and other neurological disorders. Emerging evidence has shown noncoding microRNAs (miRNAs) play crucial roles in cortical development, and their dysfunctions are associated with neurological and mental diseases. Problems are still remained to be solved in the molecular regulation mechanisms of specific miRNAs in cortical development. In our preliminary studies, we have screened a highly expressed miRNA (miR-26) that promotes proliferation of neural progenitors in the mouse embryonic cortex. Intriguingly, we found that the target gene of miR-26 has binding sites in the promoter region of its host gene. Our application is built on these preliminary data. In this proposal, we will reveal how this miRNA forms a regulatory feedback loop with its target gene and host gene, in order to precisely regulate proliferation, differentiation and migration of neural progenitors, and postmitotic neurons. The success of this project will provide essential guidelines and technical supports for further understanding miRNA-mediated brain malformations, and for developing early diagnosis tools for neurological and mental disorders.

在大脑皮层发育期，神经干细胞和神经祖细胞的异常增殖或分化，会引起大脑发育畸形，导致大脑功能失调，产生癫痫，智障等疾病。越来越多的证据显示，非编码微小RNA（microRNA，miRNA）对大脑皮层发育起到重要作用，并与人类神经和精神疾病密切相关。目前，特定的miRNA在皮层发育中精细调控的分子机理还存在许多问题亟待解决。我们的前期研究表明miR-26在小鼠胚胎大脑中特异表达，并促进神经祖细胞的分裂。此外，miR-26的靶基因Emx2可与miR-26的宿主基因Ctdsp启动子结合并激活转录。本项目推测并将验证miR-26与其靶基因Emx2、宿主基因Ctdsp形成的反馈环路调节机制，揭示miRNAs对大脑皮层神经祖细胞分裂、分化和迁移的精确控制作用。本研究为探究与miRNAs相关的大脑发育畸形病变提供新的视角，为开发神经/精神相关疾病早期诊断的新靶标奠定生物学基础。

在大脑皮层发育过程中，神经祖细胞(NPs)适宜的增殖和分化对于保障脑部的正常成形及功能发挥具有关键性作用。有证据显示，微小RNA(miRNAs)在调节大脑皮层发育及神经紊乱过程中及其重要。在本项目研究过程中，我们证实miR-26与其宿主基因Ctdsp共表达于小鼠胚胎的大脑皮层区域。我们利用miR-26过表达技术和海绵体沉默技术证实，miR-26与其宿主基因Ctdsp2都能够通过控制神经祖细胞的细胞周期进程，进而正向调控神经祖细胞的增殖过程。相反地，miR-26的靶向基因Emx2过量表达则会限制大脑皮层中神经祖细胞的扩增，但同时又会促进miR-26宿主基因Ctdsp的转录表达。这些实验数据表明，miR-26,与其靶向基因Emx2和宿主基因Ctdsp共同构成了反馈环路调控机制，在小鼠大脑皮层发育期对神经祖细胞的增殖过程进行精确调控。我们的研究成果不仅为进一步了解miRNA调控的大脑畸变提供了新的视角，也为开发神经与精神相关疾病的早期诊断提供了新的靶标。