Molecular logic of cellular diversification in the mouse cerebral cortex

Daniela J. Di Bella, Ehsan Habibi, Robert R. Stickels, Gabriele Scalia, Juliana Brown, Payman Yadollahpour, Sung Min Yang, Catherine Abbate, Tommaso Biancalani, Evan Z. Macosko, Fei Chen, Aviv Regev () and Paola Arlotta ()
Additional contact information
Daniela J. Di Bella: Harvard University
Ehsan Habibi: Harvard University
Robert R. Stickels: Broad Institute of MIT and Harvard
Gabriele Scalia: Broad Institute of MIT and Harvard
Juliana Brown: Harvard University
Payman Yadollahpour: Broad Institute of MIT and Harvard
Sung Min Yang: Harvard University
Catherine Abbate: Harvard University
Tommaso Biancalani: Broad Institute of MIT and Harvard
Evan Z. Macosko: Broad Institute of MIT and Harvard
Fei Chen: Harvard University
Aviv Regev: Broad Institute of MIT and Harvard
Paola Arlotta: Harvard University

Nature, 2021, vol. 595, issue 7868, 554-559

Abstract: 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 function1,2. However, the molecular logic that governs the establishment and organization of cortical cell types remains unknown, largely due to the large number of cell classes that undergo dynamic cell-state transitions over extended developmental timelines. Here we generate a comprehensive atlas of the developing mouse neocortex, using single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing. We sampled the neocortex every day throughout embryonic corticogenesis and at early postnatal ages, and complemented the sequencing data 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 that are linked to aberrant corticogenesis in mutant mice. The data provide a global picture of the regulatory mechanisms that govern cellular diversification in the neocortex.

Date: 2021
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DOI: 10.1038/s41586-021-03670-5

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