Oscillation of Cdc20-APC/C-mediated CAMDI stability is critical for cortical neuron migration

Radial migration during cortical development is required for formation of the six-layered structure of the mammalian cortex. Defective migration of neurons is linked to several developmental disorders such as autism and schizophrenia. A unique swollen structure called the dilation is formed in migrating neurons and is required for movement of the centrosome and nucleus. However, the detailed molecular mechanism by which this dilation forms is unclear. We report that CAMDI, a gene whose deletion is associated with psychiatric behavior, is degraded by cell division cycle protein 20 (Cdc20)-anaphase-promoting complex/cyclosome (APC/C) cell-cycle machinery after centrosome migration into the dilation in mouse brain development. We also show that CAMDI is restabilized in the dilation until the centrosome enters the dilation, at which point it is once again immediately destabilized. CAMDI degradation is carried out by binding to Cdc20-APC/C via the destruction box degron of CAMDI. CAMDI destruction box mutant overexpression inhibits dilation formation and neuronal cell migration via maintaining the stabilized state of CAMDI. These results indicate that CAMDI is a substrate of the Cdc20-APC/C system and that the oscillatory regulation of CAMDI protein correlates with dilation formation for proper cortical migration.

Automated summary

This study reveals that the CAMDI gene is degraded and restabilized in migrating neurons in the mouse brain development under the regulation of Cdc20-APC/C system, which is crucial for dilation formation and neuronal migration. These findings suggest that CAMDI plays a role in proper cortical migration through oscillatory regulation by Cdc20-APC/C system.