Interferon-γ induced medulloblastoma in the developing cerebellum

Wensheng Lin, April Kemper, Ken D. McCarthy, Peter Pytel, Jian Ping Wang, Iain L. Campbell, Manuel F. Utset, Brian Popko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

We have generated a mouse model system with a high incidence of medulloblastoma, a malignant neoplasm believed to arise from immature precursors of cerebellar granule neurons. These animals ectopically express interferon-γ (IFN-γ) in astrocytes in the CNS in a controlled manner, exploiting the tetracycline-controllable system. More than 80% of these mice display severe ataxia and develop cerebellar tumors that express synaptophysin, the mouse atonal homolog MATH1, sonic hedgehog (SHH), and Gli1. IFN-γ-induced tumorigenesis in these mice is associated with increased expression of SHH, and SHH induction and tumorigenesis are dependent on signal transducer and activator of transcription 1 (STAT1). When IFN-γ expression is shut down with doxycycline at postnatal day 12 (P12), the clinical symptoms dissipate and the mice do not develop tumors, whereas if transgene expression is shut down at P16, the clinical symptoms and tumors progress to lethality, indicating that IFN-γ is required for tumor induction but not progression. The tumors that occur in the continued presence of IFN-γ display extensive necrosis and apoptosis as well as macrophage and lymphocytic infiltration, whereas the tumors that develop in mice in which IFN-γ expression is shut down at P16 do not. Thus, IFN-γ expression in the perinatal period can induce SHH expression and medulloblastoma in the cerebellum by a STAT1-dependent mechanism, and its continued presence appears to promote a host response to the tumor.

Original languageEnglish (US)
Pages (from-to)10074-10083
Number of pages10
JournalJournal of Neuroscience
Volume24
Issue number45
DOIs
StatePublished - Nov 10 2004

Keywords

  • Cerebellum
  • Interferon-γ
  • Medulloblastoma
  • Neuroimmunomodulation
  • Signal transducer and activator of transcription
  • Sonic hedgehog
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Interferon-γ induced medulloblastoma in the developing cerebellum'. Together they form a unique fingerprint.

Cite this