During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their postmigratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location on Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their postmigratory predecessors, crossing the CP border to expand the upper cortical layers. In DSCAM-deficient cortices, migrating neurons stop prematurely under the CP border, leading to thinner upper cortical layers with higher neuronal density. We further show that DSCAM weakens cell adhesion mediated by N-cadherin in the upper cortical plate, allowing migrating neurons to traverse the CP border and expand the CP. These findings suggest that DSCAM is required for proper migratory termination and final positioning of nascent pyramidal neurons, which may provide insight into brain disorders that exhibit thinner upper layers of the cerebral cortex without neuronal loss.

SIGNIFICANCE STATEMENT Newly born neurons in the developing mammalian neocortex migrate outward toward the cortical surface, bypassing earlier born neurons to expand the developing cortex. How migrating neurons bypass the preceding neurons and terminate at the front of the expanding cortex remains poorly understood. We demonstrate that Down syndrome cell adhesion molecule (DSCAM), linked to Down syndrome and autism spectrum disorder, is required by migrating neurons to bypass their postmigratory predecessors and terminate migration in the outwardly expanding cortical layer. Migrating neurons deficient in DSCAM stop prematurely, failing to expand the cortex. We further show that DSCAM likely mediates migratory termination by weakening cell adhesion mediated by N-cadherin.

在哺乳动物新皮层发育过程中，新生的锥体神经元沿着放射状神经胶质细胞迁移并超越早期出生的神经元终止于发育中的皮层板 (CP) 的前端，导致 CP 边界向外扩展。虽然关于锥体神经元迁移的细胞和分子机制已经了解很多，但迁移神经元如何在迁移结束时绕过前面的神经元到达其最终位置仍然知之甚少。在这里，我们报告唐氏综合症细胞粘附分子 (DSCAM) 是迁移神经元在上皮质层扩张期间绕过其迁移后前辈所必需的。DSCAM 是一种 I 型跨膜细胞粘附分子。离体延时成像表明，迁移神经元需要 DSCAM 才能绕过迁移后的前辈，越过 CP 边界以扩展上皮层。在DSCAM 缺陷皮质中，迁移神经元在 CP 边界下过早停止，导致更薄的上皮质层和更高的神经元密度。我们进一步表明 DSCAM 削弱了上皮层板中 N-钙粘蛋白介导的细胞粘附，允许迁移神经元穿过 CP 边界并扩展 CP。这些发现表明，DSCAM 是新生锥体神经元正确迁移终止和最终定位所必需的，这可能有助于深入了解大脑皮层上层较薄而没有神经元丢失的脑部疾病。

意义声明发育中的哺乳动物新皮层中新生的神经元向外迁移到皮层表面，绕过较早出生的神经元以扩展发育中的皮层。迁移神经元如何绕过前面的神经元并终止于扩张皮层的前部仍然知之甚少。我们证明，与唐氏综合症和自闭症谱系障碍相关的唐氏综合症细胞粘附分子 (DSCAM) 是迁移神经元绕过其迁移后前辈并终止向外扩展的皮质层迁移所必需的。缺乏DSCAM的迁移神经元过早停止，无法扩展皮层。我们进一步表明 DSCAM 可能通过削弱 N-钙粘蛋白介导的细胞粘附来介导迁移终止。