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The Journal of Neuroscience, November 10, 2004, 24(45):10074-10083; doi:10.1523/JNEUROSCI.2604-04.2004

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Neurobiology of Disease
Interferon- Induced Medulloblastoma in the Developing Cerebellum

Wensheng Lin,¹ April Kemper,³ Ken D. McCarthy,⁴ Peter Pytel,² Jian-Ping Wang,⁵ Iain L. Campbell,⁶ Manuel F. Utset,² and Brian Popko¹

¹Jack Miller Center for Peripheral Neuropathy, Department of Neurology, and ²Department of Pathology, University of Chicago, Chicago, Illinois 60637, ³Neuroscience Center and ⁴Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, ⁵Division of Pharmacology, University of Missouri-Kansas City, Kansas City, Missouri 64108, and ⁶School of Molecular and Microbial Biosciences, The University of Sydney, Sydney, New South Wales 2006, Australia

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- (IFN-) 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--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- 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- is required for tumor induction but not progression. The tumors that occur in the continued presence of IFN- display extensive necrosis and apoptosis as well as macrophage and lymphocytic infiltration, whereas the tumors that develop in mice in which IFN- expression is shut down at P16 do not. Thus, IFN- 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.

Key words: interferon-; medulloblastoma; sonic hedgehog; signal transducer and activator of transcription; transgenic mice; neuroimmunomodulation; cerebellum

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Received June 30, 2004; revised September 28, 2004; accepted September 28, 2004.

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