Schizophrenia-linked AS3MTd2d3 Perturbs Cell Fate

The neurodevelopmental theory of schizophrenia highlights the role of early brain development in the disorder's origins. Genome-wide association studies have linked schizophrenia to genetic variations in the AS3MT gene, particularly the AS3MTd2d3 isoform. To explore this connection, we created a transgenic mouse model (AS3MTd2d3-Tg) that expresses AS3MTd2d3 in cortical neural stem cells. These mice showed enlarged ventricles and impairments in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing of AS3MTd2d3-Tg brains revealed imbalances in cell fate and changes in excitatory neuron composition. AS3MTd2d3 was found to localize to the centrosome, disrupting mitotic spindle orientation and differentiation in the developing neocortex and organoids. Structural analysis indicated that exposed hydrophobic residues in AS3MTd2d3 are crucial for its pathogenic function. These findings may shed light on the early pathological features of schizophrenia.