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

Tanzila Mukhtar (), Clara-Vita Siebert, Yuejun Wang, Mark-Phillip Pebworth, Matthew L. White, Tianzhi Wu, Tan Ieng Huang, Guolong Zuo, Jayden Ross, Jennifer Baltazar, Varun Upadhyay, Merut Shankar, Li Zhou, Isabel Lombardi-Coronel, Ishaan Mandala, Manal A. Adam, Shaohui Wang, Qiuli Bi, Marco F. M. Hoekman, Jingjing Li and Arnold R. Kriegstein ()
Additional contact information
Tanzila Mukhtar: University of California
Clara-Vita Siebert: University of California
Yuejun Wang: University of California
Mark-Phillip Pebworth: University of California
Matthew L. White: University of California
Tianzhi Wu: University of California
Tan Ieng Huang: University of California
Guolong Zuo: University of California
Jayden Ross: University of California
Jennifer Baltazar: University of California
Varun Upadhyay: University of California
Merut Shankar: University of California
Li Zhou: University of California
Isabel Lombardi-Coronel: University of California
Ishaan Mandala: University of California
Manal A. Adam: University of California
Shaohui Wang: University of California
Qiuli Bi: University of California
Marco F. M. Hoekman: University of Amsterdam
Jingjing Li: University of California
Arnold R. Kriegstein: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Prenatal nicotine exposure impairs fetal cortical grey matter volume, but the precise cellular mechanisms remain poorly understood. This study elucidates the role of nicotinic acetylcholine receptors (nAChRs) in progenitor cells and radial glia (RG) during human cortical development. We identify two nAChR subunits—CHRNA7 and the human-specific CHRFAM7A—expressed in SOX2+ progenitors and neurons, with CHRFAM7A particularly enriched along RG endfeet. nAChR activation in organotypic slices and dissociated cultures increases RG proliferation while decreasing neuronal differentiation, whereas nAChR knockdown reduces RG and increases neurons. Single-cell RNA sequencing reveals that nicotine exposure downregulates key genes in excitatory neurons (ENs), with CHRNA7 or CHRFAM7A selectively modulating these changes, suggesting an evolutionary divergence in regulatory pathways. Furthermore, we identify YAP1 as a critical downstream effector of nAChR signaling, and inhibiting YAP1 reverses nicotine-induced phenotypic alterations in oRG cells, highlighting its role in nicotine-induced neurodevelopmental pathophysiology.

Date: 2025
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DOI: 10.1038/s41467-025-61167-5

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