Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes
Warre Cornish, K.; Perfect, L.; Nagy, R.; Reid, M. J.; Mueller, A.; Evans, A.; Ghevaert, C.; McAlonan, G.; Loth, E.; Murphy, D.; Srivastava, D. P.; Price, J.
Show abstract
Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFN{gamma}), in offsprings brains play a central role. IFN{gamma} activates an antiviral cellular state, limiting viral entry and replication. In addition, IFN{gamma} has been implicated in brain development. Here, we hypothesise that IFN{gamma}-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFN{gamma} treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFN{gamma} upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFN{gamma}-induced neurite outgrowth requires both PML and MHCI. We also find that IFN{gamma} disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFN{gamma}-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.
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