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Multiple parallel cell lineages in the developing mammalian cerebral cortex

ABSTRACT: Cortical neurogenesis follows a simple lineage: apical Radial Glia Cells (RGC) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, like human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret, and barcoded lineage tracking, to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not mouse. Neurons followed parallel differentiation trajectories in gyrus and sulcus, with different expression of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mustela putorius Mustela putorius furo

PROVIDER: GSE234305 | GEO | 2024/03/27

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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Multiple parallel cell lineages in the developing mammalian cerebral cortex

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