α7 nicotinic acetylcholine receptors regulate radial glia fate in the developing human cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Prenatal nicotine exposure is linked to impaired fetal brain development, specifically reduced cortical grey matter volume.
• The precise cellular mechanisms underlying these neurodevelopmental effects remain poorly understood.

Purpose of the Study:

• To elucidate the role of nicotinic acetylcholine receptors (nAChRs) in progenitor cells and radial glia (RG) during human cortical development following prenatal nicotine exposure.
• To investigate the specific nAChR subunits involved and their downstream signaling pathways.

Main Methods:

• Utilized organotypic brain slices and dissociated cell cultures from human cortical tissue.
• Performed single-cell RNA sequencing to analyze gene expression changes in response to nicotine.
• Investigated the expression of nAChR subunits (CHRNA7, CHRFAM7A) in progenitor cells and RG.
• Assessed the impact of nAChR activation and knockdown on RG proliferation and neuronal differentiation.
• Examined the role of YAP1 as a downstream effector.

Main Results:

• Identified expression of CHRNA7 and the human-specific CHRFAM7A in SOX2+ progenitors and neurons, with CHRFAM7A enriched in RG endfeet.
• nAChR activation increased RG proliferation and decreased neuronal differentiation, while nAChR knockdown had the opposite effect.
• Nicotine exposure downregulated key genes in excitatory neurons, with CHRNA7/CHRFAM7A selectively modulating these changes.
• YAP1 was identified as a critical downstream effector, and its inhibition reversed nicotine-induced alterations in oRG cells.

Conclusions:

• Nicotinic acetylcholine receptors play a crucial role in regulating human cortical progenitor cell proliferation and neuronal differentiation.
• CHRNA7 and CHRFAM7A are key mediators of nicotine's effects on neurodevelopment.
• YAP1 signaling is a critical pathway through which nicotine exerts its neurodevelopmental pathophysiology.