Interferon-gamma Facilitates Neurogenesis by Activating Wnt/ß-catenin Cell Signaling Pathway via Promotion of STAT1 Regulation of the ß-Catenin Promoter.

Interferon-gamma (IFN-γ) is critical for central nervous system (CNS) functions and it may be a promising treatment to stimulate CNS regeneration. However, previous studies reported inconsistent results, and the molecular mechanisms remain controversial. Here we show that IFN-γ-treated mice via intraperitoneal injection have elevated IFN-γ level in central hippocampus and superior cognitive behaviors IFN-γ could activates the level of protein expression of Wnt7a, ß-catenin, and CyclinD1 in Wnt/ß-catenin signaling pathway of mice hippocampus. Functional and mechanism analysis in vitro revealed that IFN-γ promoted the proliferation and differentiation in primary cultured neural stem cells (NSCs). STAT1 was accountable for IFN-γ-induced activation of the ß-catenin promoter, and IFN-γ increased the binding affinity of STAT1 to ß-catenin promoter based on luciferase activity and chromatin immunoprecipitation. Our results suggest that IFN-γ exerts many effects ranging from cognitive function in vivo to NSC proliferation, self-renewal, and differentiation in vitro. It does so by recruiting STAT1 to the ß-catenin promoter, enhancing cis-regulation by STAT1, and ultimately activating Wnt/ß-catenin signaling. In this study, we first found that STAT1 was recruited into the promoter of ß-catenin to activate ß-catenin expression, and this effect was regulated by IFN-γ. It is also discovered firstly that Wnt/ß-catenin and JAK/STAT pathways form cross-links through STAT1. Promoting neurogenesis through immune stimulation might be a promising strategy for repairing the diseased/injured CNS. This study provides a scientific basis for immunomodulation to promote nerve regeneration and offer a new therapeutic direction for central nervous system regeneration.