α7 nicotinic acetylcholine receptors regulate radial glia fate in the developing human cortex
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.
Authors
- Jayden Ross (ORCID: https://orcid.org/0000-0002-5569-8624)
- Arnold R. Kriegstein (ORCID: https://orcid.org/0000-0001-5742-2990)
- Marco F.M. Hoekman
- Tianzhi Wu
- Jennifer Baltazar
- Clara Siebert (ORCID: https://orcid.org/0000-0001-9009-5442)
- Manal A. Adam (ORCID: https://orcid.org/0000-0002-1590-063X)
- Mark-Phillip Pebworth (ORCID: https://orcid.org/0000-0001-8224-9480)
- Tanzila Mukhtar (ORCID: https://orcid.org/0000-0001-9646-8940)
- Jingjing Li (ORCID: https://orcid.org/0000-0001-6025-9522)
- Varun Upadhyay
- Qiuli Bi
- Tao Huang (ORCID: https://orcid.org/0009-0005-6676-8463)
- Shaohui Wang (ORCID: https://orcid.org/0000-0002-4203-4941)
- Li Zhou (ORCID: https://orcid.org/0000-0003-3874-4833)
- Yuejun Wang (ORCID: https://orcid.org/0000-0002-8491-4082)
- Matthew L. White (ORCID: https://orcid.org/0009-0003-6000-7626)
- Guolong Zuo (ORCID: https://orcid.org/0000-0003-1214-8849)
- Malini Shankar
- Isabel Lombardi-Coronel
- Ishaan Mandala
Institutions
- University of California, San Francisco (US)
- Allen Institute (US)
- Broad Center (US)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41467-025-61167-5
- Citations
- 1
- Primary Topic
- Nicotinic Acetylcholine Receptors Study
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Science Foundation
- Boehringer Ingelheim Fonds
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health