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

CXCL12 调节大脑皮层尾部神经节隆起衍生的 GABA 能神经元的迁移和最终层分配

• 批准号: 391088085
• 负责人: Professor Dr. Ralf Stumm
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391088085?language=en
• 关键词: CXCL12; regulates; migration; final; layer

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.

大脑皮层gaba能神经元（中间神经元）是一种高度特化的异质细胞群，对皮层网络活动施加必要的抑制控制。这些神经元发育的缺陷导致神经系统疾病，也可能导致神经精神疾病。我们研究了这些神经元的迁移是如何在个体发生过程中受到调节的。大约70%的中间神经元起源于内侧神经节隆起（mGE）， 30%起源于尾神经节隆起（cGE）。cge衍生的中间神经元在其祖细胞、遗传程序和功能方面与mge衍生的中间神经元不同。它们的生成也较晚，在出生后的皮质发生过程中经历独特的表面定向迁移，并主要整合到浅层（mge衍生的中间神经元均匀分布在第II-VI层）。目前尚不清楚是哪些引导分子组织了cge衍生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的CXCL12信号传导对于mge衍生的中间神经元的早期迁移至关重要。虽然CXCL12对这些细胞的最终分层只有很小的影响，但在中间神经元前体中CXCL12/CXCR4通路的缺陷调节与精神分裂症的病理生物学有关。我们现在证明，在CXCL12信号模块缺陷的小鼠中，cge衍生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在皮质发生后期在许多cge来源的中间神经元中保持表达，而在大多数mge来源的细胞中被关闭。我们在子宫内建立了电穿孔、活细胞显微镜和独特的遗传工具，使我们能够验证这样的假设，即时间CXCR4表达谱的差异有助于大脑皮层中不同的迁移行为和中间神经元亚型的分层。