Interferon-gamma induced medulloblastoma in the developing cerebellum.
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-gamma (IFN-gamma) 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-gamma-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-gamma 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-gamma is required for tumor induction but not progression. The tumors that occur in the continued presence of IFN-gamma display extensive necrosis and apoptosis as well as macrophage and lymphocytic infiltration, whereas the tumors that develop in mice in which IFN-gamma expression is shut down at P16 do not. Thus, IFN-gamma 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.
Lin
Wensheng
W
Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, Illinois 60637, USA.
Kemper
April
A
McCarthy
Ken D
KD
Pytel
Peter
P
Wang
Jian-Ping
JP
Campbell
Iain L
IL
Utset
Manuel F
MF
Popko
Brian
B
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002524:Cerebellar Ataxia / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter; D005813:Genes, Synthetic; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D053823:Hedgehog Proteins; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007763:Lac Operon; D007962:Leukocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008527:Medulloblastoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D015213:Neuroimmunomodulation / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004318:Doxycycline; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D007371:Interferon-gamma; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; C500943:Atoh1 protein, mouse; C465570:Shh protein, mouse; C494080:Stat1 protein, mouse