Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

Journal article

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-γ (IFN-γ), in offspring's brains play a central role. IFN-γ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-γ is implicated in brain development. We tested the hypothesis that IFN-γ signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-γ treatment of neural progenitors derived from human induced pluripotent stem cells increased neurite outgrowth. RNA sequencing analysis revealed that major histocompatibility complex class I (MHCI) genes were persistently up-regulated through neuronal differentiation-an effect that was mediated by IFN-γ-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-γ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-γ disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-γ signaling in neurodevelopmental disorder etiology.

Authors: Warre-Cornish, K; Perfect, L; Nagy, R; Duarte, RRR; Reid, MJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science Advances
• Volume: 6
• Issue: 34
• Pages: eaay9506-eaay9506
• Publication date: 2020-08-19
• DOI: 10.1126/sciadv.aay9506
• EISSN: 2375-2548
• ISSN: 2375-2548
• Language: English
• Keywords: Gene expression; Interferon; Genetics; Phenotype; Gene; Neuroscience; Medicine; Neurodevelopmental disorder; Biology; Immunology; Transcriptome