Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex

Projection neurons migrate from the ventricular zone to the neocortical plate during mouse brain development. Their overall movement is radial, but they become multipolar and move non-radially in the intermediate zone. Here we show that Reelin, the Rap1 GTPase, and N-cadherin (NCad) are important for multipolar neurons to polarize their migration towards the cortical plate. Inhibition and rescue experiments indicate that Reelin regulates migration through Rap1 and Akt, and that Rap1-regulated GTPases, RalA/B, Rac1 and Cdc42, are also involved. We find that Rap1 regulates plasma membrane localization of N-cadherin, and N-cadherin rescues radial polarization when Rap1 is inhibited. Curiously, inhibition of Rap1 or N-cadherin has little effect on glia-dependent locomotion. We propose a multi-step mechanism in which Reelin activates Rap1, Rap1 up-regulates N-cadherin, and N-cadherin is needed to orient cell migration.