Voss Anne K, Britto Joanne M, Dixon Mathew P, Sheikh Bilal N, Collin Caitlin, Tan Seong-Seng, Thomas Tim
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Development. 2008 Jun;135(12):2139-49. doi: 10.1242/dev.016725.
Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration.
神经元迁移是大脑皮层发育和高级脑功能的重要组成部分。皮层神经元迁移缺陷会导致诸如无脑回畸形和癫痫等精神障碍。神经元与其细胞外环境的相互作用通过细胞表面受体调节皮层神经元迁移。然而，细胞外基质蛋白发出的信号如何在细胞内转导尚不清楚。我们在此报告，缺乏Ras家族鸟嘌呤核苷酸交换因子C3G（Rapgef1，Grf2）的小鼠胚胎表现出皮层神经元迁移缺陷，导致无法将前板分裂为边缘区和亚板，也无法形成皮层板。C3G缺陷的皮层神经元无法迁移。相反，它们停滞在多极状态并在前板下方聚集。在C3G缺陷的大脑中，基底膜被破坏，放射状胶质细胞突起紊乱且缺乏附着。C3G在皮层神经元中对Reelin产生反应而被激活，进而导致小GTP酶Rap1的激活。在C3G缺陷的细胞中，对Reelin刺激的反应中Rap1的GTP负载减少。总之，Ras家族调节因子C3G对皮层发育的两个方面至关重要，即放射状胶质细胞附着和神经元迁移。
