Abstract
Correct development of the cerebellum requires coordinated sonic hedgehog (Shh) signaling from Purkinje to granule cells. How Shh expression is regulated in Purkinje cells is poorly understood. Using a novel tyrosinase minigene-tagged Sleeping Beauty transposon-mediated mutagenesis, which allows for coat color-based genotyping, we created mice in which the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene is deleted. Loss of Skor2 leads to defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Skor2 is specifically expressed in Purkinje cells in the brain, where it is required for proper expression of Shh. Skor2 overexpression suppresses BMP signaling in an HDAC-dependent manner and stimulates Shh promoter activity, suggesting that Skor2 represses BMP signaling to activate Shh expression. Our study identifies an essential function for Skor2 as a novel transcriptional regulator in Purkinje cells that acts upstream of Shh during cerebellum development.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Morphogenetic Proteins / metabolism
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Cell Differentiation
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Cerebellum / abnormalities
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Cerebellum / growth & development*
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Cerebellum / metabolism*
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Gene Expression Regulation, Developmental
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Genotype
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Hair Color / genetics
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Hedgehog Proteins / genetics*
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Hedgehog Proteins / metabolism*
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Histone Deacetylases / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Monophenol Monooxygenase / genetics
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Mutagenesis, Insertional
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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Purkinje Cells / cytology
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Purkinje Cells / metabolism
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Repressor Proteins / deficiency
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism*
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Signal Transduction
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Transforming Growth Factor beta / metabolism
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Transposases / genetics
Substances
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Bone Morphogenetic Proteins
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Corl2 protein, mouse
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Hedgehog Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Shh protein, mouse
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Skil protein, mouse
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Transforming Growth Factor beta
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Monophenol Monooxygenase
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Transposases
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sleeping beauty transposase, human
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Histone Deacetylases