α2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2
α2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2
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DOI：
10.1038/nn.2972
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发表时间：
2012-01-01
影响因子：
25
通讯作者：
Ip, Nancy Y.
中科院分区：
文献类型：
--
作者：
Ip, Jacque P. K.;Shi, Lei;Ip, Nancy Y.
皮质神经元迁移中断与癫痫发作和发育迟缓有关。然而，早期皮质发育中断导致神经系统症状的分子机制知之甚少。在这里，我们报告α 2-嵌合蛋白作为皮质神经元迁移和功能的关键调节。在子宫内抑制α 2-嵌合蛋白逮捕神经元迁移在多极阶段，导致异位神经元在皮质下区域的积累。具有这种迁移缺陷的小鼠表现出局部皮质回路中兴奋和抑制之间的不平衡，并且对惊厥诱导的癫痫发作更敏感。我们进一步表明，α 2-chimaerin调节双极转换和神经元迁移通过调节CRMP-2，微管相关蛋白的活性。这些研究结果建立了一个新的α 2-嵌合蛋白依赖性机制的神经元迁移和大脑皮层的正常功能，并提供了深入了解的发病机制与神经发育障碍。
Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report alpha 2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppression of alpha 2-chimaerin arrested neuronal migration at the multipolar stage, leading to accumulation of ectopic neurons in the subcortical region. Mice with such migration defects showed an imbalance between excitation and inhibition in local cortical circuitry and greater susceptibility to convulsant-induced seizures. We further show that alpha 2-chimaerin regulates bipolar transition and neuronal migration through modulating the activity of CRMP-2, a microtubule-associated protein. These findings establish a new alpha 2-chimaerin-dependent mechanism underlying neuronal migration and proper functioning of the cerebral cortex and provide insights into the pathogenesis of seizure-related neurodevelopmental disorders.