Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding

Sisu Han, Satoshi Okawa, Grey Atteridge Wilkinson, Hussein Ghazale, Lata Adnani, Rajiv Dixit, Ligia Tavares, Imrul Faisal, Matthew J. Brooks, Veronique Cortay, Dawn Zinyk, Adam Sivitilli, Saiqun Li, Faizan Malik, Yaroslav Ilnytskyy, Vladimir Espinosa Angarica, Jinghua Gao, Vorapin Chinchalongporn, Ana Maria Oproescu, Lakshmy VasanYacine Touahri, Luke Ajay David, Eko Raharjo, Jung Woong Kim, Wei Wu, Waleed Rahmani, Jennifer Ai wen Chan, Igor Kovalchuk, Liliana Attisano, Deborah Kurrasch, Colette Dehay, Anand Swaroop, Diogo S. Castro, Jeff Biernaskie, Antonio del Sol, Carol Schuurmans*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2847-2863.e11
Issue number18
Publication statusPublished - 15 Sept 2021


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


Dive into the research topics of 'Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding'. Together they form a unique fingerprint.

Cite this