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First published online May 23, 2008
doi: 10.1242/10.1242/dev.016725
1 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050,
Australia.
2 Department of Medical Biology, University of Melbourne, Parkville 3010,
Victoria, Australia.
3 Howard Florey Institute, Parkville, 3010 Victoria, Australia.
* Authors for correspondence (e-mails: avoss{at}wehi.edu.au; tthomas{at}wehi.edu.au)
Accepted 18 April 2008
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.
Key words: Neuronal migration, Cerebral cortex, Radial glia, Reelin, Cell adhesion, Ras signalling pathway, Mouse
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