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Interferon-? signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes.

ABSTRACT: Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-? (IFN-?), in offspring's brains play a central role. IFN-? activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-? is implicated in brain development. We tested the hypothesis that IFN-? signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-? 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-?-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-?-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-? disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-? signaling in neurodevelopmental disorder etiology.

SUBMITTER: Warre-Cornish K

PROVIDER: S-EPMC7438100 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Warre-Cornish Katherine K Perfect Leo L Nagy Roland R Duarte Rodrigo R R RRR Reid Matthew J MJ Raval Pooja P Mueller Annett A Evans Amanda L AL Couch Amalie A Ghevaert Cédric C McAlonan Grainne G Loth Eva E Murphy Declan D Powell Timothy R TR Vernon Anthony C AC Srivastava Deepak P DP Price Jack J

Science advances 20200819 34

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 deri ...[more]

PMID: 32875100

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Interferon-? signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes.

Publications

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

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