Neurons maintain sequential order during radial migration by DSCAM-facilitated antagonism of N-Cadherin

ABSTRACT Proper migration and positioning of migrating pyramidal neurons occur in an “inside-out” pattern and are vital for proper cortico-genesis. The contribution of factors produced by migrating neurons in the morphogenesis of a developing cerebral cortex remains largely unknown. Our previous research revealed that a radial-migrating neuron must navigate to bypass its post-migratory predecessor, which resides at the dorsal border of the developing cortical plate, before reaching its final position. This final stage of radial migration ensures adherence to the “inside-out” pattern at the cellular level. However, whether neurons consistently preserve their sequential order during the prolonged radial migration period remains uncertain. In this study, we found that nascent neurons form queues perpendicular to the cortical plate during radial migration, extending across the upper cortical plate by approximately embryonic day 19. Within each queue, the leading neuron acts as a barrier, restricting the radial migration of the following neuron to preserve their order. We further discovered that the Down syndrome cell adhesion molecule (DSCAM) functions cell-type autonomously in both the leading and following neurons to maintain their sequential order. We find that DSCAM in neurons is necessary to generate a gap between migrating neurons by suppressing N-cadherin-mediated adhesion. Without N-cadherin adhesion, the trailing neuron fails to assemble F-actin at the proximal end of the leading process, preventing its expansion and subsequently hindering nucleokinesis. In Dscam null mutant or Cre-induced knock-out, this gap is not observed, allowing N-cadherin adhesion to persist. Consequently, all migrating neurons keep moving directly to the dorsal border of the cortical plate, and the queue of migrating neurons does not form. This research reveals that DSCAM preserves the sequential order of neurons during radial migration, playing a crucial role in “inside-out” cortico-genesis. Competing Interest Statement The authors have declared no competing interest.