Rab23 Regulates Radial Migration of Projection Neurons via PDGFRα-Mediated Expression of N-cadherin (Abstract)

Radial migration of cortical projection neurons is a prerequisite for shaping a distinct multi-layered cerebral cortex during mammalian corticogenesis. Members of Rab GTPases family were reported to regulate radial migration. Here, in vivo conditional-knockout or in utero knockdown (KD) of Rab23 in mice neocortex cause aberrant polarity and halted migration of cortical projection neurons. Further investigation of underlying mechanism reveals down-regulation of N-cadherin in the Rab23-deficient neurons, which is a cell adhesion protein previously known to modulate radial migration. Interestingly, pharmacological inhibition of ERK1/2 also decreases the expression of N-cadherin, implicating an upstream effect of ERK1/2 on N-cadherin and also suggesting a link between Rab23 and ERK1/2. Further biochemical studies showed that silencing of Rab23 impedes activation of ERK1/2 via perturbed PDGFRα signaling. Restoration the expression of Rab23 or N-cadherin in Rab23-KD neurons could reverse neuron migration defects, indicating that Rab23 modulates migration through N-cadherin. These studies suggest that cortical neuron migration is mediated by a molecular hierarchy downstream of Rab23 via PDGFRα signaling pathway.