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.

doi:10.1101/789321

bioRxiv · 10.1101/789321

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.

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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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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.. 2019-10-04. Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes. https://doi.org/10.1101/789321

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