CXCL12 regulates migration and final layer allocation of caudal ganglionic eminence-derived GABAergic neurons in the cerebral cortex

大脑皮质的GABA能神经元(中间神经元)是一种高度专业化的异质细胞群，对皮质网络活动起着基本的抑制控制作用。这些神经元发育的缺陷会导致神经和可能的神经精神障碍。我们研究了这些神经元的迁移在个体发育过程中是如何受到调节的。约70%的中间神经元起源于内侧神经节隆起(MGE)，30%起源于尾侧神经节隆起(CGE)。CGE来源的中间神经元在祖细胞、遗传程序和功能方面不同于MGE来源的中间神经元。它们也是较晚产生的，在出生后皮质生成期间经历独特的表面定向迁移，并大多整合到表层(MGE来源的中间神经元均匀分布在II-VI层)。目前尚不清楚是哪些引导分子组织了CGE来源的中间神经元的迁移和分层。我们和其他人证实，通过趋化因子受体CXCR4传递的CXCL12信号对于MGE来源的中间神经元的早期迁移至关重要。尽管CXCL12对这些细胞的最终分层只有很小的影响，但CXCL12/CXCR4通路在神经元前体中的调节缺陷与精神分裂症的病理生物学有关。我们现在证明，在CXCL12信号模块有缺陷的小鼠中，CGE来源的中间神经元的迁移和最终分层受到严重干扰。我们还发现，CXCR4在许多CGE来源的中间神经元中的表达在皮质发生后期保持不变，而在大多数MGE来源的细胞中被关闭。我们建立了宫内电穿孔、活细胞显微镜和独特的遗传工具，使我们能够测试这一假说，即时间CXCR4表达谱的这种差异有助于大脑皮层中间神经元亚型的不同迁移行为和分层。

GABAergic neurons of the cerebral cortex (interneurons) are a highly specialized heterogeneous cell population that exerts essential inhibitory control over cortical network activity. Defects in the development of these neurons lead to neurological and probably neuropsychiatric disorders. We investigate how the migration of these neurons is regulated during ontogenesis. Approximately 70% of interneurons originate in the medial ganglionic eminence (mGE) and 30% in the caudal ganglionic eminence (cGE). cGE-derived interneurons are distinct from their mGE-derived counterparts with regard to their progenitors, genetic programs and functions. They are also generated later, undergo unique surface-directed migration during postnatal corticogenesis and integrate mostly into superficial layers (mGE-derived interneurons are homogeneously distributed across layers II-VI). Little is known which guidance molecules organize migration and layering of cGE-derived interneurons. We and others established that CXCL12 signaling through the chemokine receptor CXCR4 is essential for early migration of mGE-derived interneurons. Although CXCL12 has only small effects on final layering of these cells, defective regulation of the CXCL12/CXCR4 pathway in interneuron precursors has been implicated in the pathobiology of schizophrenia. We now demonstrate that migration and final layering of cGE-derived interneurons are severely perturbed in mice with defects in the CXCL12 signaling module. We also found that CXCR4 expression is maintained in many cGE-derived interneurons during late corticogenesis while being switched off in most mGE-derived cells. We established in utero electroporation, live cell microscopy and unique genetic tools enabling us to test the hypothesis that such differences in the temporal CXCR4 expression profile contribute to different migration behavior and layering of interneuron subtypes in the cerebral cortex.