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学科主题: 医学神经生物学
题名:
表观遗传因子CDYL在神经元迁移中的作用研究
作者: 秦瑞
答辩日期: 2016-11-22
导师: 王韵
专业: 医学神经生物学
授予单位: 北京大学
授予地点: 北京大学基础医学院
学位: 博士
关键词: CDYL ; 神经元迁移 ; 转录调控 ; RhoA ; 癫痫
其他题名: The role of epigenetic factor CDYL in neuronal migration
分类号: Q189
摘要:

在哺乳动物大脑的发育过程中,新生神经元的正确迁移是大脑正常发育,形成环路,行使功能的一个必不可少的环节。神经元迁移的异常会导致一系列严重的神经精神疾病,如自闭症,癫痫和精神分裂症等。研究神经元迁移的分子机制对于理解这些疾病的发病过程和寻找新的治疗靶点具有重要意义。神经元的迁移受到胞外因素,细胞质组分和细胞核过程的协同调控,最近的研究表明细胞核内的生物学过程,尤其是表观遗传在神经元的迁移过程中发挥着重要的作用。CDYL(Choromo-domain Y Like)是一个新发现的转录共抑制子,我们前期的研究发现CDYL能够与EZH2协同作用调控神经元树突分支的复杂程度。

在本课题中我们主要研究了CDYL在神经元迁移中的作用。我们综合运用生物化学,分子生物学,形态学,电生理学,行为学等实验方法发现:CDYL的表达量随着大脑皮层的发育逐渐降低,在小鼠的胚胎发育期含量最高,成年后含量明显减少;CDYL条件敲除小鼠的皮层神经元迁移出现异常,用胚胎颅内电转的方法敲低CDYL不影响神经细胞的增殖,凋亡和命运,却能够显著抑制神经元的迁移,通过全长的CDYL和N端删减突变的CDYL的挽救实验证实CDYL调控神经元迁移依赖于其 N-端的染色质结合结构域;敲低CDYL是通过影响神经元由多极向双极的转变来抑制神经元迁移的;进一步的研究显示,敲低CDYL会使RhoA的表达量增加同时使微丝切割蛋白cofilin的磷酸化水平升高,而敲低RhoA或过表达磷酸化突变的cofilin能够挽救由敲低CDYL导致的神经元迁移变慢。此外,我们还发现条件敲除CDYL不影响小鼠的情绪与学习记忆能力,而敲低CDYL会使神经元的兴奋性增加,同时增强小鼠的癫痫易感性。

通过以上研究,我们证明了CDYL在神经发育早期阶段的重要作用。CDYL的缺失会使神经元的迁移发生障碍,并且影响神经元的生理功能,这为理解神经发育和神经发育性疾病的分子机制提供了新的启示。

英文摘要:

During the development of the mammalian brain, the correct migration of new born neurons is one of the determinants for circuit formation. Disrupted cortical neuronal migration is associated with many psychiatric disorders, such as autism, schizophrenia and epilepsy. Underlying the molecular mechanisms of neuronal migration is important for understanding the pathogenesis of these diseases,and searching for new therapeutic targets. It has been known that extracellular factors, cytosol fraction and the nucleus process act coordinately to regulate neuronal migration. Recent studies revealed that nucleus process, especially the epigenetic regulation is critical for neuronal migration. Our previous work find that Chromo domain Y-like protein, a recently discovered tranion co-repressor,which coordinately regulating dendrite arborization with EZH2.

In this study, we focus on the role of CDYL during neuronal migration. Using a series of experiments with molecular biology, cell biology, morphology and animal behavior tests, we found that: The protein level of CDYL decreased as the brain matures, with the highest level present at embryonic days 14-18 (E14-18). Neuronal migration is abnormal in Cdyl conditional knockout mice. Knocking down CDYL by in utero electroporation does not affect the proliferation, apoptosis or cell fate, however, the neuronal migration is defected in CDYL silenced neurons. The rescue experiments demonstrate the effects of CDYL on neuronal migration are dependent on its omodomain which is responsible for omatain association. Knocking down CDYL inhibited neuronal migration by disrupting the mobility and multipolar-bipolar transition of the migrating neurons. Further analysis shows that RhoA expression and the phosphorylation of cofilin were increased when knockdown CDYL. In addition, either knockdown RhoA or overexpression of S3A cofilin can rescue the migration defects induced by knocking down CDYL. Moreover, we found CDYL deficiency doesnot affect the emotion and learning and memory of mice, but increases the excitability of cortical pyraal neurons and the susceptibility of mice to convulsant-induced seizures.

Taken together, we demonstrated the function of CDYL in the early neural development. CDYL deficiency disrupts neuronal migration and physiological function. This study sheds new light on the understanding of the molecular mechanisms of neural development and neural developmental disorders.

语种: 中文
相关网址: 查看原文
内容类型: 学位论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/125094
Appears in Collections:基础医学院_学位论文

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作者单位: 北京大学基础医学院

Recommended Citation:
秦瑞. 表观遗传因子CDYL在神经元迁移中的作用研究[D]. 北京大学基础医学院. 北京大学. 2016.
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