Molecular Logic of Cellular Diversification in the Mouse Cerebral Cortex

Abstract

The mammalian cerebral cortex has an unparalleled diversity of cell types, which are generated during development through a series of temporally orchestrated events that are under tight evolutionary constraint and are critical for proper cortical assembly and function. However, the molecular logic that governs the establishment and organization of cortical cell types remains elusive, largely due to the large number of cell classes undergoing dynamic cell-state transitions over extended developmental timelines. Here, we have generated a comprehensive single-cell RNA-seq and single-cell ATAC-seq atlas of the developing mouse neocortex, sampled every day throughout embryonic corticogenesis and at early postnatal ages, complemented with a spatial transcriptomics time-course. We computationally reconstruct developmental trajectories across the diversity of cortical cell classes, and infer their spatial organization and the gene regulatory programs that accompany their lineage bifurcation decisions and differentiation trajectories. Finally, we demonstrate how this developmental map pinpoints the origin of lineage-specific developmental abnormalities linked to aberrant corticogenesis in mutant animals. The data provides a global picture of the regulatory mechanisms governing cellular diversification in the neocortex.