Migrating Pyramidal Neurons Require DSCAM to Bypass the Border of the Developing Cortical Plate

• Published in: The Journal of neuroscience Vol. 42; no. 28; pp. 5510 - 5521
• Main Authors: Yang, Tao, Veling, Macy W, Zhao, Xiao-Feng, Prin, Nicholas P, Zhu, Limei, Hergenreder, Ty, Liu, Hao, Liu, Lu, Rane, Zachary S, Savelieff, Masha G, Fuerst, Peter G, Li, Qing, Kwan, Kenneth Y, Giger, Roman J, Wang, Yu, Ye, Bing
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 13.07.2022
• Subjects: Adhesion; Adhesive strength; Autism; Cadherins; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cerebral cortex; Chromosome 21; Disorders; Down syndrome; Down's syndrome; DSCAM protein; Glial cells; Mammals; Molecular modelling; Mutation; N-Cadherin; Neocortex; Neural cell adhesion molecule; Neuroimaging; Neuronal-glial interactions; Neurons; Pyramidal cells; Radial glial cells; Trisomy; cortex development; termination; migration; pyramidal neuron; DSCAM; cell adhesion
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0997-21.2022

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. 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 -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. 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 stop prematurely, failing to expand the cortex. We further show that DSCAM likely mediates migratory termination by weakening cell adhesion mediated by N-cadherin.