Perturbed cell fate decision by schizophrenia-associated AS3MT^d2d3 isoform during corticogenesis

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Schizophrenia is linked to neurodevelopmental factors.
• Genome-wide association studies implicate the AS3MT gene, particularly the AS3MT^d2d3 isoform, in schizophrenia risk.

Purpose of the Study:

• To investigate the biological mechanisms linking AS3MT^d2d3 expression to schizophrenia pathophysiology.
• To establish and characterize a transgenic mouse model (AS3MT^d2d3-Tg) for studying AS3MT^d2d3's role in brain development.

Main Methods:

• Generated AS3MT^d2d3-Tg mice with ectopic AS3MT^d2d3 expression in cortical neural stem cells.
• Performed behavioral analyses (sensorimotor gating, sociability) and neuroanatomical assessments (ventricle size).
• Utilized single-cell and single-nucleus RNA sequencing to analyze brain cell composition and gene expression. Investigated AS3MT^d2d3 localization and interactions using structural and cellular biology techniques.

Main Results:

• AS3MT^d2d3-Tg mice displayed enlarged ventricles and deficits in sensorimotor gating and sociability.
• RNA sequencing revealed cell fate imbalances and altered excitatory neuron composition in AS3MT^d2d3-Tg brains.
• AS3MT^d2d3 localized to the centrosome, disrupting mitotic spindle orientation and neural differentiation, partly via NPM1. Hydrophobic residues in AS3MT^d2d3 were critical for its pathogenic function.

Conclusions:

• Ectopic expression of AS3MT^d2d3 in neural stem cells leads to neurodevelopmental abnormalities relevant to schizophrenia.
• AS3MT^d2d3's disruption of cell division and differentiation provides a potential molecular mechanism for early schizophrenia pathogenesis.
• This transgenic mouse model offers a valuable tool for further research into schizophrenia's genetic and developmental origins.