Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway.
Here we examined the role of interferon (IFN)-gamma in regulating the Sonic hedgehog (Shh) pathway and cerebellar development in bigenic mice with temporal control of IFN-gamma gene expression driven by a tetracycline-controllable promoter. In IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing bigenic or control mice, development of the cerebellum was severely affected with the persistence and extensive proliferation of the external granule neuron layer (EGL) and infiltration with modest numbers of T-lymphocytes. Following induction of IFN-gamma transgene expression, both total and tyrosine-phosphorylated signal transducer and activator of transcription (STAT)1 (the major transcriptional factor for IFN-gamma), phosphorylated STAT3 and STAT5, and expression of a number of IFN-gamma-regulated genes were significantly increased in cerebellum. In the cerebellum from IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing mice, the level of Shh and Gli-1 but not Patched (Ptch) 1 RNA was increased as was the 19-kDa signaling product of the Shh precursor protein. In situ localization studies revealed ectopic expression of the Shh gene by the granule neurons. We conclude that IFN-gamma directly affects the proliferation and fate of EGL neurons in the cerebellum by activating the Shh pathway and stimulating an autocrine growth response by these cells.
Wang
Jianping
J
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Lin
Wensheng
W
Popko
Brian
B
Campbell
Iain L
IL
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053823:Hedgehog Proteins; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
D004268:DNA-Binding Proteins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D007371:Interferon-gamma; D004318:Doxycycline