DSCAM preserves neuronal order during radial migration by antagonizing N-Cadherin adhesion and UNC5c repulsion

Yang, T., Hergenreder, T., Veling, M. W., Chang, W.-C., Cui, E. J., Wang, Y., Fuerst, P. G., Giger, R. J., Zhao, X.-F.

10.1101/2025.06.16.659927 · was preprinted

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Abstract

Proper radial migration of developing cortical neurons is critical for the "inside-out" laminar organization of the mammalian cerebral cortex. While substantial progress has been made in our understanding of how neurons terminate migration at the cortical plate (CP)/marginal layer (ML) boundary, the mechanisms that control the sequential order of migrating neurons remain poorly understood. Here, we show that radial migration of upper-layer pyramidal neurons is transiently restrained within the upper cortical plate (UCP), where migrating neurons assemble into vertically organized radial queues that maintain inter-neuronal spacing and migratory order. Using time-lapse imaging of embryonic mouse cortex, we found that leading neurons transiently delay nucleokinesis of trailing neurons, thereby synchronizing neuronal movement within the UCP. Loss of Down syndrome cell adhesion molecule (DSCAM) disrupts this coordinated migratory behavior, allowing trailing neurons to bypass preceding neurons, resulting in abnormal neuronal accumulation near the CP/ML boundary. Mechanistically, DSCAM localizes to membrane interfaces between adjacent migrating neurons. At these sites, DSCAM suppresses N-cadherin-mediated intercellular adhesion, limits F-actin assembly, and inhibits expansion of the proximal cytoplasmic dilation required for nucleokinesis. Dscam-deficient neurons exhibit increased cadherin puncta, more neuron-neuron contacts, and accelerated migration through the UCP. Rescue experiments demonstrate that expressing the extracellular domain of Dscam is sufficient to restore ordered migration, suggesting that an extracellular mechanism regulates orderly neuronal migration. In addition, we identify UNC5c-mediated signaling as a counterbalancing force that promotes upward migration within the UCP. Together, our findings identify radial neuronal queues as a previously unrecognized intermediate structure in cortical morphogenesis and establish DSCAM-dependent regulation of inter-neuronal spacing as a mechanism that preserves the migratory order during inside-out corticogenesis.

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biorxiv v2 2026-07-09 source ↗

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