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Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-α–stimulated STAT2-independent production of IFN-γ in the brain
Jianping Wang, … , Christian Schindler, Iain L. Campbell
Jianping Wang, … , Christian Schindler, Iain L. Campbell
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):535-543. https://doi.org/10.1172/JCI18637.
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Article Neuroscience

Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-α–stimulated STAT2-independent production of IFN-γ in the brain

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Abstract

The type I IFNs (IFN-α and IFN-β), which are crucial in antiviral defense and immune regulation, signal via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway with activation of STAT1 and STAT2. Here, the function of STAT2 was studied in transgenic mice (termed GIFN/STAT2–/–) with CNS production of IFN-α. Surprisingly, GIFN/STAT2–/–, but not GIFN/STAT1-null, transgenic mice, with CNS production of IFN-α, died prematurely with medulloblastoma. An immune response also induced in the brain of the GIFN/STAT2–/– mice was associated with IFN-γ gene expression by CD3+ T cells and the activation of the STAT1, STAT3, STAT4, and STAT5 molecules. Expression of the Sonic hedgehog (Shh) and the downstream transcriptional factor Gli-1 genes, implicated in the pathogenesis of medulloblastoma, was found to be significantly increased and cotranscribed in cerebellar granule neurons of the GIFN/STAT2–/– mice. IFN-γ, but not IFN-α, induced STAT1-dependent expression of the Shh gene in cultured cerebellar granule neurons. Thus, there is an unexpected and extraordinarily adverse biological potency of IFN-α in the CNS when the primary signal transduction molecule STAT2 is absent. Moreover, a hitherto unknown role is indicated for the immune system in the pathogenesis of developmental disorders and tumorigenesis of the CNS via dysregulated Shh signaling mediated by IFN-γ.

Authors

Jianping Wang, Ngan Pham-Mitchell, Christian Schindler, Iain L. Campbell

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Figure 4

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Activation of the Shh signaling pathway. (a) RNase protection analysis o...
Activation of the Shh signaling pathway. (a) RNase protection analysis of Shh, Gli-1, and Ptch1 mRNAs (n = 5–7, **P < 0.01 compared with control groups). (b) Total-protein lysates (100 μg per sample) from the cerebellum of 3-week-old mice were immunoblotted with anti-Shh, anti–Shh-N, and anti-actin (sample loading control) antibodies. (c) Localization by in situ hybridization of Shh and Gli-1 mRNA transcripts in the cerebellum of 3-week-old mice. (d) Expression of the Shh and STAT1 genes by cultured granule neurons. Cells were exposed to either IFN-α (upper panel) or IFN-γ (lower panel) for 4 hours at 37°C. Total RNA was then prepared and analyzed by RPA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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