C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment.
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.
Voss
Anne K
AK
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. avoss@wehi.edu.au
Britto
Joanne M
JM
Dixon
Mathew P
MP
Sheikh
Bilal N
BN
Collin
Caitlin
C
Tan
Seong-Seng
SS
Thomas
Tim
T
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology*; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D009154:Mutation; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D000091042:Reelin Protein; D013234:Stem Cells / Q000166:cytology
D020735:Guanine Nucleotide-Releasing Factor 2; D000091042:Reelin Protein; C000717128:Reln protein, mouse