Abstract
Mechanisms that control vascular smooth muscle cell (SMC) differentiation are poorly understood. We identify Pitx2 as a previously unknown homeodomain transcription factor that is rapidly induced in an in vitro model of SMC differentiation from multipotent stem cells. Pitx2 induces expression of multiple SMC differentiation marker genes by binding to a TAATC(C/T) cis-element, by interacting with serum response factor, and by increasing histone acetylation levels within the promoters of SMC differentiation marker genes. Suppression of Pitx2 reduces expression of SMC differentiation marker genes in the early stages of SMC differentiation in vitro, whereas Prx1, another homeodomain protein, regulates SMC differentiation marker genes in fully differentiated SMCs. Pitx2, but not Prx1, knockout mouse embryos exhibit impaired induction of SMC differentiation markers in the dorsal aorta and branchial arch arteries. Our results demonstrate that Pitx2 functions to regulate the early stages of SMC differentiation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Biomarkers / metabolism
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Cell Differentiation / physiology*
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Cells, Cultured
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / physiology
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Gene Expression Regulation
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Histone Deacetylase 2
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Histones / metabolism
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Homeobox Protein PITX2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Mice
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Mice, Knockout
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Muscle, Smooth, Vascular / cytology*
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / physiology*
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Serum Response Factor / genetics
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Serum Response Factor / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Two-Hybrid System Techniques
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / metabolism
Substances
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Biomarkers
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Histones
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Homeodomain Proteins
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Prrx1 protein, mouse
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RNA, Small Interfering
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Repressor Proteins
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Serum Response Factor
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Transcription Factors
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Hdac2 protein, mouse
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Hdac5 protein, mouse
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Histone Deacetylase 2
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Histone Deacetylases