Perturbed cell fate decision by schizophrenia-associated AS3MTisoform during corticogenesis.

Abstract

The neurodevelopmental theory of schizophrenia emphasizes early brain development in its etiology. Genome-wide association studies have linked schizophrenia to genetic variations of(arsenite methyltransferase) gene, particularly the increased expression of AS3MTisoform. To investigate the biological basis of this association with schizophrenia pathophysiology, we established a transgenic mouse model (AS3MT-Tg) ectopically expressing AS3MTat the cortical neural stem cells. AS3MT-Tg mice exhibited enlarged ventricles and deficits in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing analyses of AS3MT-Tg brains revealed cell fate imbalances and altered excitatory neuron composition. AS3MTlocalized 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 AS3MTare critical for its pathogenic function. Therefore, our findings may help to explain the early pathological features of schizophrenia.