Interferon-gamma (IFN-gamma) is one of the critical cytokines released by host immune cells upon infection. Despite the important role(s) of IFN-gamma in host immune responses, there has been no in vivo study regarding the effects of IFN-gamma on brain development, and the results from many in vitro studies are controversial. In this study, the effects of IFN-gamma on embryonic neurogenesis were investigated. Treatment of E14.5 mouse neural progenitor cells (NPCs) with IFN-gamma resulted in a decrease in the percentage of TuJ1-positive immature neurons but an increase in the percentage of Nestin-positive NPCs. Similar results were obtained in vivo. Treatment of NPCs with a JAK inhibitor or the knockdown of STAT1 expression abrogated the IFN-gamma-mediated inhibition of neurogenesis. Interestingly, the expression of one of proneural genes, Neurogenin2 (Neurog2) was dramatically inhibited upon IFN-gamma treatment, and cells overexpressing Neurog2 did not respond to IFN-gamma. Taken together, our results demonstrate that IFN-gamma inhibits neuronal differentiation of NPCs by negatively regulating the expression of Neurog2 via the JAK/STAT1 pathway. Our findings may provide an insight into the role of IFN-gamma in the development of embryonic brain. (C) 2015 Elsevier Inc. All rights reserved.