Perturbed cell fate decision by schizophrenia-associated AS3MT <sup>d2d3</sup> isoform during corticogenesis
The neurodevelopmental theory of schizophrenia emphasizes early brain development in its etiology. Genome-wide association studies have linked schizophrenia to genetic variations of <i>AS3MT</i> (arsenite methyltransferase) gene, particularly the increased expression of AS3MT<sup>d2d3</sup> isoform. To investigate the biological basis of this association with schizophrenia pathophysiology, we established a transgenic mouse model (AS3MT<sup>d2d3</sup>-Tg) ectopically expressing AS3MT<sup>d2d3</sup> at the cortical neural stem cells. AS3MT<sup>d2d3</sup>-Tg mice exhibited enlarged ventricles and deficits in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing analyses of AS3MT<sup>d2d3</sup>-Tg brains revealed cell fate imbalances and altered excitatory neuron composition. AS3MT<sup>d2d3</sup> localized to centrosome, disrupting mitotic spindle orientation and differentiation in developing neocortex and organoids, in part through NPM1 (Nucleophosmin 1). The structural analysis identified that hydrophobic residues exposed in AS3MT<sup>d2d3</sup> are critical for its pathogenic function. Therefore, our findings may help to explain the early pathological features of schizophrenia.
Authors
- Truong Thi My Nhung (ORCID: https://orcid.org/0000-0003-3432-9464)
- Bon Seong Goo (ORCID: https://orcid.org/0000-0002-5457-4224)
- Jin Yeong Yoo (ORCID: https://orcid.org/0000-0003-0526-3638)
- Wonhyeok Lee
- Inseop Chun (ORCID: https://orcid.org/0000-0002-0050-0836)
- Hongkai Ji (ORCID: https://orcid.org/0000-0002-6480-0141)
- Su-Jin Noh (ORCID: https://orcid.org/0000-0002-2312-1740)
- Dahun Um (ORCID: https://orcid.org/0000-0002-7668-1629)
- Tran Diem Nghi
- Yeongjun Suh (ORCID: https://orcid.org/0000-0002-1841-4792)
- Ki Hurn So
- Namyoung Jung (ORCID: https://orcid.org/0000-0003-0027-5330)
- Jia Yun (ORCID: https://orcid.org/0000-0003-4694-3111)
- Tae-Kyung Kim (ORCID: https://orcid.org/0000-0001-5161-9864)
- Sang Ki Park (ORCID: https://orcid.org/0000-0003-1023-7864)
- Jong‐Cheol Rah (ORCID: https://orcid.org/0000-0003-3780-0522)
- Dae‐Kyum Kim (ORCID: https://orcid.org/0000-0003-4568-8278)
- Dong Jin Mun
- Seung Tae Baek (ORCID: https://orcid.org/0000-0003-0040-1501)
- Ki‐Jun Yoon (ORCID: https://orcid.org/0000-0003-2985-2541)
- Seunghyun Kim (ORCID: https://orcid.org/0009-0002-3963-7079)
- Min‐Sung Kim (ORCID: https://orcid.org/0000-0002-2369-9956)
- Young Sik Woo (ORCID: https://orcid.org/0000-0002-8308-8532)
- Hyunsoo Jang (ORCID: https://orcid.org/0000-0001-9191-3697)
- Su Been Lee (ORCID: https://orcid.org/0000-0003-2919-207X)
- Songyan Han
Institutions
- Pohang University of Science and Technology (KR)
- Korea Advanced Institute of Science and Technology (KR)
- McGill University Health Centre (CA)
- Advanced Institute of Convergence Technology (KR)
- Korea Brain Research Institute (KR)
- McGill University (CA)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1126/sciadv.adp8271
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00