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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 1

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GIFN mice lacking STAT2 die prematurely with medulloblastoma. (a) Surviv...
GIFN mice lacking STAT2 die prematurely with medulloblastoma. (a) Survival curves for GIFN/STAT2–/– mice compared with GIFN/STAT1–/– mice and other control mice (n = 8–10 mice per group). (b) Gross pathology of the brain. Sagittal brain sections (10 μm) stained with H&E, showing considerable enlargement of the cerebellum due to diffusely spreading medulloblastoma and hydrocephalus (asterisks) in 3-week-old GIFN/STAT2–/– mice compared with age-matched WT, GIFN, and GIFN/STAT1–/– mice. (c) Sagittal section (10 μm) through the cerebellum of a 3-week-old GIFN/STAT1–/– mouse, showing abnormal presence and hyperplasia of the external germinal layer (arrow) and early tumor formation (asterisk). (d) H&E-stained section through a medulloblastoma in the cerebellum of a GIFN/STAT2–/– mouse. The tumors were composed of small, darkly stained cells with a sparse cytoplasm and prominent nucleus. Numerous mitotic figures were evident (arrows). (e) Sagittal frozen section (10 μm) through a medulloblastoma from a GIFN/STAT2–/– mouse, immunostained for PCNA. Original magnifications: ×1 for b; ×4 for c; ×600 for d; ×400 for e.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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