在大脑皮层发育过程中，神经前体细胞会不断的增殖，新生的神经元要不断迁移以适应大脑皮层发育的需要。皮层神经元迁移对于皮层结构和神经环路的形成至关重要。已有研究表明细胞骨架微管对于皮层神经元的迁移至关重要。微管的性质和功能可以受到其组成蛋白α-tubulin和β-tubulin翻译后修饰的调节，其中第40位赖氨酸上乙酰化修饰的α-tubulin在神经系统高度富集，被公认为是稳定性微管的标志，参与调节微管与动力蛋白的结合。但是α-tubulin乙酰化修饰在神经发育过程中的作用还不清楚。
9月13日，《神经科学杂志》发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所鲍岚研究组的研究工作：发现α-tubulin的主要乙酰基转移酶MEC-17在大脑皮层发育过程中高表达。通过在体干扰MEC-17的表达可以显著抑制皮层投射神经元的迁移，在抑制性中间神经元发生区MGE的体外培养组织中干扰MEC-17表达同样可以抑制中间神经元的迁移。MEC-17水平降低会阻碍皮层神经元在迁移过程中从多极向双极的转换。进一步的研究表明，干扰MEC-17可以显著降低皮层神经元α-tubulin第40位赖氨酸上的乙酰化水平，通过降低α-tubulin去乙酰化酶HDAC6或者过表达模拟乙酰化的α-tubulinK40Q突变体可以显著恢复MEC-17水平降低引起的皮层神经元迁移和转换异常。该研究揭示了MEC-17和α-tubulin的乙酰化在大脑皮层发育过程中的重要作用，阐述了微管蛋白α-tubulin通过翻译后修饰影响大脑皮层发育的细胞机制。该项工作由博士研究生李磊等在鲍岚研究员的指导下完成。
该工作得到了中国科学院、国家自然科学基金、科技部蛋白质重大研究计划等项目的资助。（生物谷Bioon.com）
doi: 10.1523/JNEUROSCI.0016-12.2012
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MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons
Lei Li, Dan Wei, Qiong Wang, Jing Pan, Rong Liu, Xu Zhang, and Lan Bao
Neuronal migration is a fundamental process during the development of the cerebral cortex and is regulated by cytoskeletal components. Microtubule dynamics can be modulated by posttranslational modifications to tubulin subunits. Acetylation of α-tubulin at lysine 40 is important in regulating microtubule properties, and this process is controlled by acetyltransferase and deacetylase. MEC-17 is a newly discovered α-tubulin acetyltransferase that has been found to play a major role in the acetylation of α-tubulin in different species in vivo. However, the physiological function of MEC-17 during neural development is largely unknown. Here, we report that MEC-17 is critical for the migration of cortical neurons in the rat. MEC-17 was strongly expressed in the cerebral cortex during development. MEC-17 deficiency caused migratory defects in the cortical projection neurons and interneurons, and perturbed the transition of projection neurons from the multipolar stage to the unipolar/bipolar stage in the intermediate zone of the cortex. Furthermore, knockdown of α-tubulin deacetylase HDAC6 or overexpression of tubulinK40Q to mimic acetylated α-tubulin could reduce the migratory and morphological defects caused by MEC-17 deficiency in cortical projection neurons. Thus, MEC-17, which regulates the acetylation of α-tubulin, appears to control the migration and morphological transition of cortical neurons. This finding reveals the importance of MEC-17 and α-tubulin acetylation in cortical development.
