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August 15, 2003Journal of Clinical InvestigationOpen Access

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

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Authors

JWJianping WangNPNgan Pham-MitchellCSChristian Schindler

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Overview

Transgenic mouse study demonstrates medulloblastoma driven by interferon-gamma and Sonic hedgehog signaling in STAT2-deficient mice, indicating an immune pathway promoting brain tumors.

Key Points

  • To evaluate the role of STAT2 in mediating central nervous system responses to localized interferon-alpha expression.
  • Examined transgenic mice engineered with central nervous system interferon-alpha expression lacking STAT2 (GIFN/STAT2-/-) compared to STAT1-deficient counterparts (GIFN/STAT1null).
  • Assessed immune activation, T-cell cytokine production, and Sonic hedgehog pathway gene expression in cerebellar granule neurons in vivo and in cell culture.
  • GIFN/STAT2-/- mice died prematurely with medulloblastoma, whereas GIFN/STAT1null mice with identical interferon-alpha expression did not develop brain tumors.
  • Brain tissue in GIFN/STAT2-/- mice exhibited CD3+ T-cell infiltration with interferon-gamma expression and activation of STAT1, STAT3, STAT4, and STAT5.
  • Sonic hedgehog (Shh) and Gli-1 mRNA levels increased significantly in cerebellar granule neurons, with interferon-gamma directly inducing STAT1-dependent Shh expression in vitro.

Cite This Study

Wang et al. (2003) studied this question.

synapsesocial.com/papers/6a86691c4c7902adb32fdfd2https://doi.org/10.1172/jci200318637
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