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

ABSTRACT: Folding 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 the Flrt1/3 double 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

ORGANISM(S): Mus musculus

PROVIDER: GSE267391 | GEO | 2025/05/20

REPOSITORIES: GEO

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Project description:Our brains accommodate a largely folded cerebral cortex that associates to our advanced brain functions. Several theories have been proposed to explain the cortical folding process, reasoning the mechanical forces as neuronal tension in underlying layers, cellular expansion and glial progenitor’s diversity in the OSVZ; but the mechanistic insights and underlying genomics changes causing the appearance of cortical folds is still illusive. Importantly, no studies have attempted to comprehensively characterize the gene regulatory networks underlying cortical folding during development. Here, by using ferret as a model system, we have compared the transcriptomes of germinal layers between sulci and gyri, of different cortical areas and across two developmental stages (E30 & E34), to achieve a comprehensive understanding of the spatio-temporal dynamics of gene expression of cortical progenitors. Furthermore, we have also characterized the epigenetic landscape of germinal layers at E30 and E34, a critical period for their development, to correlate changes in chromatin at promoter and enhancer regions with the observed changes in gene expression. Our preliminary results indicate towards a clear transformational axis of gene regulation between germinal layers. By performing motif analysis of differentially expressed gene (DEGs), we reveal transcription factors which might have a critical role in determining cortical folding. The genes targeted by these factors belong to important pathways implicated in proliferation and neurogenesis. We highlight potential candidates in cortical folding through functional validation studies and acetylation (H3K27ac) levels for these genes correlate with their expression state. Importantly, these are critical for cell adhesion, migration and proliferation processes in-line with previous studies stating that proliferative divisions cause neocortical expansions. Our findings will have strong impact on the clinical interventions for neurological disorders relating to cortical malformation, while at the same time enhancing our understanding of molecular circuitry underlying gyrencephalic brain development and folding.

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

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