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

Area of Science:

• Developmental Neuroscience
• Evolutionary Biology
• Genetics

Background:

• Asymmetric neuronal expansion is key to evolutionary changes between smooth (lissencephalic) and folded (gyrencephalic) cerebral cortices.
• The roles of proneural genes in maintaining neurogenic continuity and brain structure are not fully understood.

Purpose of the Study:

• To investigate the function of Neurog2 and Ascl1 proneural genes in sustaining neurogenic continuity and lissencephaly.
• To identify the specific neural progenitor cell (NPC) populations involved in cortical development and folding.

Main Methods:

• Utilized transgenic reporter mice and human cerebral organoids to study Neurog2 and Ascl1 expression patterns.
• Employed a split-Cre system with diphtheria toxin to selectively eliminate specific NPC populations.
• Analyzed Notch signaling pathways and gene regulatory networks in different NPC pools.

Main Results:

• Identified four lineage-biased NPC pools defined by Neurog2 and Ascl1 expression, forming a developmental continuum.
• Discovered that double-positive (Double+) NPCs exhibit multipotency features, including open chromatin and G2 cell cycle pausing.
• Selective elimination of Double+ NPCs disrupted Notch signaling, altered neurogenic symmetry, and induced cortical folding.
• Observed modular transcript distribution of NEUROG2, ASCL1, and HES1 in gyrencephalic macaque cortices, mirroring future fold patterns.

Conclusions:

• The interplay between Neurog2 and Ascl1 sustains neurogenic continuity and lissencephaly.
• Double+ NPCs act as critical niche cells, regulating neurogenic periodicity and cortical folding through Notch signaling.
• These findings provide insights into the cellular and genetic mechanisms driving evolutionary transitions in cerebral cortex morphology.