Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a critical role in neuronal migration during neocortical development. However, the molecular insights of these processes remain elusive. Here we study an early endosomal protein Smad Anchor for Receptor Activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of mouse neocortex. While silencing SARA did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibit impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA-silenced neurons exhibit increased surface expression of L1, a cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA silencing, and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-caused phenotypes. SARA-silenced neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localized at more superficial cortical layers compared to their controls counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition, and positioning of cortical neurons via modulating surface L1 expression.
- Received August 4, 2015.
- Accepted July 17, 2016.