PT  - JOURNAL ARTICLE
AU  - Sisu Han
AU  - Grey A Wilkinson
AU  - Satoshi Okawa
AU  - Lata Adnani
AU  - Rajiv Dixit
AU  - Imrul Faisal
AU  - Matthew Brooks
AU  - Veronique Cortay
AU  - Vorapin Chinchalongporn
AU  - Dawn Zinyk
AU  - Saiqun Li
AU  - Jinghua Gao
AU  - Faizan Malik
AU  - Yacine Touahri
AU  - Vladimir Espinosa Angarica
AU  - Ana-Maria Oproescu
AU  - Eko Raharjo
AU  - Yaroslav Ilnytskyy
AU  - Jung-Woong Kim
AU  - Wei Wu
AU  - Waleed Rahmani
AU  - Igor Kovalchuk
AU  - Jennifer Ai-wen Chan
AU  - Deborah Kurrasch
AU  - Diogo S. Castro
AU  - Colette Dehay
AU  - Anand Swaroop
AU  - Jeff Biernaskie
AU  - Antonio del Sol
AU  - Carol Schuurmans
TI  - Proneural genes define ground state rules to regulate neurogenic patterning and cortical folding
AID  - 10.1101/2020.09.22.307058
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.22.307058
4099  - http://biorxiv.org/content/early/2020/09/22/2020.09.22.307058.short
4100  - http://biorxiv.org/content/early/2020/09/22/2020.09.22.307058.full
AB  - Transition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show that Neurog2 and Ascl1 proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissencephalic rodent brain. Using in vivo lineage tracing, we found that Neurog2 and Ascl1 expression defines a lineage continuum of four progenitor pools, with ‘double+ progenitors’ displaying several unique features (least lineage-restricted, complex gene regulatory network, G2 pausing). Strikingly, selective killing of double+ progenitors using split-Cre;Rosa-DTA transgenics breaks neurogenic symmetry by locally disrupting Notch signaling, leading to cortical folding. Finally, consistent with NEUROG2 and ASCL1 driving discontinuous neurogenesis and folding in gyrencephalic species, their transcripts are modular in folded macaque cortices and pseudo-folded human cerebral organoids. Neurog2/Ascl1 double+ progenitors are thus Notch-ligand expressing ‘niche’ cells that control neurogenic periodicity to determine cortical gyrification.HIGHLIGHTSNeurog2 and Ascl1 expression defines four distinct transitional progenitor statesDouble+ NPCs are transcriptionally complex and mark a lineage branch pointDouble+ NPCs control neurogenic patterning and cortical folding via Notch signalingNeurog2 and Ascl1 expression is modular in folded and not lissencephalic corticeseTOC BLURB Emergence of a gyrencephalic cortex is associated with a break in neurogenic continuity across the cortical germinal zone. Han et al. identify a pool of unbiased neural progenitors at a lineage bifurcation point that co-express Neurog2 and Ascl1 and produce Notch ligands to control neurogenic periodicity and cortical folding.Competing Interest StatementThe authors have declared no competing interest.