Cortex Folding by Combined Progenitor Expansion and Adhesion-Controlled Neuronal Migration

Abstract

SUMMARYFolding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we find that combining theFlrt1/3double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 results in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 results in enhanced formation of gyri. Single cell transcriptomics and simulations suggest that changes in adhesive properties of cortical neurons, their proportions and densities in the cortical plate, combined with lateral dispersion during their radial migration are important folding parameters. These results identify key developmental mechanisms that cooperate to promote cortical gyrification.HIGHLIGHTSCortex folding is enhanced by combining progenitor expansion and divergent migration.Concomitant expansion of intermediate progenitors results in the formation of sulciConcomitant expansion of apical progenitors results in the formation of gyriProgenitors differentially affect cortical neurons with distinct adhesive properties