Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the 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 the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-induced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.
The authors declare no competing or financial interests.
Conceptualization: I.M., C.-H.S.; Methodology: I.M., J.-Z.C.; Formal analysis and investigation: I.M.; Writing – original draft preparation: I.M.; Writing – review and editing: I.M., C.-H.S.; Funding acquisition: I.M., C.C., C.-H.S., F.C.; Resources: C.C., F.C.; Supervision: C.-H.S., J.-Z.C.
This work was supported by the National Eye Institute (NEI) of the National Institutes of Health (NIH) [EY11307 and EY016805], Starr Foundation, and Research to Prevent Blindness to C.-H.S. Travel grants from Journal of Cell Science/The Company of Biologists and the International Society for Neurochemistry, and a Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) fellowship were awarded to I.M. The Center for Regenerative Therapies Dresden, Technische Universität Dresden and Deutsche Forschungsgemeinschaft Collaborative Research Center SFB655 (subproject A20) supported F.C. PICT 2008-0671 from the Ministerio de Ciencia, Tecnología e Innovación Productiva was granted to C.C. Deposited in PMC for release after 12 months.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.129338.supplemental
- Received August 4, 2015.
- Accepted July 17, 2016.