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