Neuron
Volume 109, Issue 18, 15 September 2021, Pages 2847-2863.e11
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Article
Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding

https://doi.org/10.1016/j.neuron.2021.07.007Get rights and content
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Highlights

  • Neurog2 and Ascl1 proneural gene expression defines four transitional NPC states

  • Neurog2-Ascl1 cross-repress to block lineage bias of double+ NPCs at hierarchy apex

  • Double+ NPCs direct uniform neurogenesis via Notch to sustain murine lissencephaly

  • NEUROG2, ASCL1, and HES1 expression is modular in gyrencephalic macaque cortices

Summary

Asymmetric neuronal expansion is thought to drive evolutionary transitions between lissencephalic and gyrencephalic cerebral cortices. We report that Neurog2 and Ascl1 proneural genes together sustain neurogenic continuity and lissencephaly in rodent cortices. Using transgenic reporter mice and human cerebral organoids, we found that Neurog2 and Ascl1 expression defines a continuum of four lineage-biased neural progenitor cell (NPC) pools. Double+ NPCs, at the hierarchical apex, are least lineage restricted due to Neurog2-Ascl1 cross-repression and display unique features of multipotency (more open chromatin, complex gene regulatory network, G2 pausing). Strikingly, selectively eliminating double+ NPCs by crossing Neurog2-Ascl1 split-Cre mice with diphtheria toxin-dependent “deleter” strains locally disrupts Notch signaling, perturbs neurogenic symmetry, and triggers cortical folding. In support of our discovery that double+ NPCs are Notch-ligand-expressing “niche” cells that control neurogenic periodicity and cortical folding, NEUROG2, ASCL1, and HES1 transcript distribution is modular (adjacent high/low zones) in gyrencephalic macaque cortices, prefiguring future folds.

Keywords

neocortex
proneural genes
neural progenitor cells
transcriptome
epigenome
gene regulatory network
Notch signaling
cortical folding
neural lineages
lineage priming

Data and Code Availability

  • RNA-seq and ATAC-seq data were deposited at GEO, ChIP-seq data was deposited at Array Express, and uncropped western blot images were deposited in Mendeley data at Mendeley. Accession numbers are listed in the Key Resources Table. These data are publicly available as of the date of publication. All other data reported in this study will be shared by the lead contact upon request.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this work paper is available from the Lead Contact upon request.

Cited by (0)

17

Present address: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-sen University, Guangzhou 510060, China

18

Present address: Department of Life Science, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea

19

Present address: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

20

These authors contributed equally

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Lead contact