遗传 ›› 2019, Vol. 41 ›› Issue (6): 524-533.doi: 10.16288/j.yczz.19-123

• 研究报告 • 上一篇    下一篇

Bmal1对小鼠胚胎期皮层神经元放射状迁移和轴突投射的影响

李芳1,黄青芸2,刘斯佳1,2,3,4,郭忠信1,2,3,4,熊欣欣1,桂林2,束会娟1,黄绍明1,4,谭国鹤1,2,3,4(),刘媛媛1,2,3,4()   

  1. 1. 广西医科大学基础医学院,南宁 530021
    2. 广西生物医药协同创新中心,广西再生医学重点实验室,南宁 530021
    3. 广西医科大学转化医学研究中心,长寿与老年相关疾病教育部重点实验室,南宁 530021
    4. 广西特色新型智库—中国-东盟脑科学创新发展研究中心,南宁 530021;
  • 收稿日期:2019-05-05 修回日期:2019-05-28 出版日期:2019-06-20 发布日期:2019-06-05
  • 通讯作者: 谭国鹤,刘媛媛 E-mail:tanguohe@gxmu.edu.cn;382890945@qq.com
  • 作者简介:李芳,硕士研究生,专业方向:人体解剖与组织胚胎学。E-mail:1689795367@qq.com
  • 基金资助:
    广西研究生教育创新计划项目(YCSW2018115);广西研究生教育创新计划项目(YCSW2017113);广西研究生教育创新计划项目(YCSW2019102);广西研究生教育创新计划项目(JGY2017039);广西"新世纪十百千人才工程"项目(201501);广西杰出青年基金项目(2015GXNSFGA139005);广西科技基地与人才专项资助(AD17195079)

The role of Bmal1 in neuronal radial migration and axonal projection of the embryonic mouse cerebral cortex

Li Fang1,Huang Qingyun2,Liu Sijia1,2,3,4,Guo Zhongxin1,2,3,4,Xiong Xinxin1,Gui Lin2,Shu Huijuan1,Huang Shaoming1,4,Tan Guohe1,2,3,4(),Liu Yuanyuan1,2,3,4()   

  1. 1. School of Preclinical Medicine of Guangxi Medical University, Nanning 530021, China
    2. Guangxi Collaborative Innovation Center for Biomedicine and Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning 530021, China
    3. Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Center for Translational Medicine, Guangxi Medical University, Nanning 530021, China
    4. China-ASEAN Research Center for Innovation and Development in Brain Science, Nanning 530021, China
  • Received:2019-05-05 Revised:2019-05-28 Online:2019-06-20 Published:2019-06-05
  • Contact: Tan Guohe,Liu Yuanyuan E-mail:tanguohe@gxmu.edu.cn;382890945@qq.com
  • Supported by:
    Supported by the Innovation Project of Guangxi Graduate Education(YCSW2018115);Supported by the Innovation Project of Guangxi Graduate Education(YCSW2017113);Supported by the Innovation Project of Guangxi Graduate Education(YCSW2019102);Supported by the Innovation Project of Guangxi Graduate Education(JGY2017039);The New Centuary Ten, Hundred, and Thousand Talent Project of Guangxi Province(201501);The Natural Science Foundation for Distinguished Young Scholars of Guangxi Province(2015GXNSFGA139005);The Special Project for Platforms and Talents of Science and Technology Foundation of Guangxi Province(AD17195079)

摘要:

大脑皮层的发育是脑结构形成与功能建立的重要基础,在此过程中,皮层神经元放射状迁移及胼胝体区的轴突投射是必不可少的关键环节,该环节受基因转录的调控,但相关的分子机制目前仍不明确。转录因子BMAL1 (brain and muscle Arnt-like protein1)是体内重要的生物钟节律因子之一,最新研究发现其还参与调节海马神经祖细胞增殖,提示其与神经发育存在潜在的相关性。为明确Bmal1基因在大脑皮层发育中的具体作用,本研究首先通过RT-PCR和Real-time PCR检测Bmal1基因在神经系统中的表达情况。结果表明,Bmal1基因在神经系统中表达丰富,并且在发育期的大脑内呈现特定的表达规律:在胚胎后期和出生后早期脑内表达水平相对较高,以出生后第3 d为高峰。进一步通过联合使用小鼠子宫内胚胎电转和RNAi干扰方法敲减脑内神经元中Bmal1的表达水平,结果发现胚胎期皮层神经元的放射状迁移发生了延迟,延迟程度与RNAi的敲减效率呈正相关,存在一定的基因剂量-效应关系。进一步观察发现,在胚胎期脑内神经元中降低Bmal1表达水平以后,胼胝体轴突向对侧大脑半球的投射也出现了明显的缺陷。上述研究结果表明,BMAL1是大脑皮层神经元的放射状迁移以及轴突投射发育过程中的一个重要的调控分子,为从转录因子角度深入理解大脑皮层发育的分子调节机制和寻找调控靶点提供了新的线索。

关键词: 大脑皮层发育, Bmal1, 神经元迁移, 轴突投射, 子宫内胚胎电转

Abstract:

Normal development of the cerebral cortex is a basis for the formation and function of mammalian brains. During this process, the radial migration of cortical neurons, as well as the axon projection into specific layers, are the most important steps regulated by some transcription factors, but the underlying molecular mechanisms are still obscure. BMAL1 (brain and muscle Arnt-like protein 1) is a newly identified transcription factor that plays important roles in the circadian rhythms. It was recently found to regulate the proliferation of hippocampal neuronal progenitor/precursor cells (NPCs), implicating Bmal1 in the brain development. Here we employed both RT-RCR and real-time PCR to explore the expression pattern of the Bmal1 gene in the developing brain. We found BMAl1 is enriched in the brain cortex during the perinatal stages and peaked in P3 mouse brains. Combined with in utero electroporation and interference with RNAi, we found that reducing the expression level of Bmal1 in neurons, the radial migration of embryonic cortical neurons was largely delayed, in a gene dose-effect pattern. Moreover, reducing the level of Bmal1 expression in mouse brains, the axonal projection in the corpus callosum was also disrupted from ipsilateral to the lateral cerebral hemisphere. These findings indicate that BMAL1 is essential for the radial migration of neurons in the cerebral cortex and the axonal projection of the corpus callosum, providing insights into the molecular mechanisms of cerebral cortex development.

Key words: cortical development, Bmal1, neuronal migration, axon projection, in utero electroporation