title: Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development.
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.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Baiping
authors.initials: B
authors.lastname: Wang
authors.forename: Wilbur
authors.initials: W
authors.lastname: Harrison
authors.forename: Paul A
authors.initials: PA
authors.lastname: Overbeek
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002531:Cerebellum / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000235:genetics; D016254:Mutagenesis, Insertional; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019895:Transposases / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; C532058:Corl2 protein, mouse; D053823:Hedgehog Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C465570:Shh protein, mouse; C486157:Skil protein, mouse; D016212:Transforming Growth Factor beta; D014442:Monophenol Monooxygenase; D019895:Transposases; C494471:sleeping beauty transposase, human; D006655:Histone Deacetylases