A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that is critical for innate and adaptive immunity. Recent evidence suggests a connection between IFN-gamma signaling and the sonic hedgehog (Shh) pathway in the developing brain with CNS-targeted expression of IFN-gamma transgene in mice. To determine the relationship between these distinct pathways, we have found that IFN-gamma induces a rapid Shh transcription in cultured primary granular neuron precursor (GNP) cells. The transcriptional induction of Shh by IFN-gamma is resistant to protein synthesis inhibition. Chromatin immunoprecipitation (ChIP) analysis reveals a direct binding of signal transducer and activator of transcription (STAT) 1 to the Shh promoter. Functional analyses, including dual immunofluorescent labeling with 5-bromodeoxyuridine (BrdU) incorporation indicate that IFN-gamma treatment leads to significant GNP proliferation. This mitogenic effect of IFN-gamma is blocked by inhibition of Shh signaling. Therefore, Shh is an IFN-gamma target gene and is responsible for IFN-gamma-induced GNP proliferation. This previously unrecognized cross-talk between IFN-gamma and Shh highlights a potential importance of this immune mediator in the pathogenesis of human developmental and psychiatric disorders.