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

Abstract

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.

Comprehensive cell atlas of the first-trimester developing human brain

“…Closer examination of gene expression differences between neurons and neuroblasts showed that genes critical for neuronal migration in the mouse were induced in the neuron class cells, including DAB1, VLDLR and DSCAM ( 16, 17 ). In contrast, genes that are uniquely expressed in the germinal zone, such as PPP17R1 and NEUROD4 were observed in neuroblasts ( 18, 19 ) (table S4).…”

Analysis of Mouse Brain Sections by Live-cell Time-lapse Confocal Microscopy

“…In our recent paper, Migrating pyramidal neurons require DSCAM to bypass the border of the developing cortical plate , we described the termination process of neuron radial migration and reported a molecular mechanism that underlies this process ( Yang et al, 2022 ). We found that the nascent pyramidal neuron bypassing the last preceding neuron is important for expanding the cortex and thus determines the thickness of the upper cortical layers.…”

“…In our study, we applied live cell time-lapse imaging on organotypic brain-slice cultures to observe the termination of radial migration in detail ( Yang et al, 2022 ). Organotypic brain slice cultures preserve brain development within an ex vivo environment.…”

“…As we realized that our approach could be used as a standard method for studying cortical development and be extended to other brain regions or tissues, we decided to report our protocol in detail here, so that other researchers can reference, modify, and optimize their own imaging system. For the sake of completeness, we include brief protocols for neuronal labeling and brain slice sectioning in the “animal preparation” section, although these techniques have been previously described ( Yang et al, 2022 ).…”

Modeling congenital brain malformations with brain organoids: a narrative review

“…RG cells have the capacity for self-renewal to expand the neural progenitor cells (NPCs) pool and can differentiate into intermediate progenitor cells or neurons directly ( 2 , 3 ). The newborn neurons then migrate to their final destinations in the different layers of the cerebral cortex ( 4 , 5 ). Dysfunctions of early neurodevelopment, including neurogenesis and neural migration, have been associated with structural malformations of the human brain.…”