Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report α2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppression of α2-chimaerin arrested neuronal migration at the multipolar stage, leading to accumulation of ectopic neurons in the subcortical region. Mice with such migration defects showed an imbalance between excitation and inhibition in local cortical circuitry and greater susceptibility to convulsant-induced seizures. We further show that α2-chimaerin regulates bipolar transition and neuronal migration through modulating the activity of CRMP-2, a microtubule-associated protein. These findings establish a new α2-chimaerin-dependent mechanism underlying neuronal migration and proper functioning of the cerebral cortex and provide insights into the pathogenesis of seizure-related neurodevelopmental disorders.
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- Supplementary Text and Figures (2M)
Supplementary Figures 1–11
- Supplementary Video 1 (623K)
This movie shows the migration of neurons electroporated with pSUPER vector and GFP plasmids. Most of the neurons attained bipolar shape, underwent nuclear translocation and migrated up to the cortical plate. Images were captured every 15 min for 13 h.
- Supplementary Video 2 (606K)
This movie shows the migration of neurons electroporated with α2-chimerin shRNA and GFP plasmids. α2-chimerin knockdown neurons were unable to enter into the cortical plate, and showed local movement within the intermediate zone. Images were captured every 15 min for 13 h.
- Supplementary Video 3 (602K)
This movie shows an example of migrating neurons electroporated with pSUPER vector and GFP plasmids. The neuron extended and retracted neurites actively, and eventually formed one major leading process guiding the migration of cell body towards pial surface. Images were captured every 10 min for 7 h.
- Supplementary Video 4 (627K)
This movie shows an example of migrating neurons electroporated with α2-chimerin shRNA and GFP plasmids. The neuron showed impaired neurite dynamics and failed to form a leading process towards pial surface. Images were captured every 10 min for 7 h.