The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels.
The ATP-dependent chromatin-remodeling enzyme brahma-related gene 1 (BRG1) regulates transcription of specific target genes during embryonic and postnatal development. Deletion of Brg1 from embryonic blood vessels results in yolk sac vascular remodeling defects. We now report that misregulation of the canonical Wnt signaling pathway underlies many Brg1 mutant vascular phenotypes. Brg1 deletion resulted in down-regulation of several Wnt receptors of the frizzled family, degradation of the intracellular Wnt signaling molecule β-catenin, and an overall decrease in Wnt signaling in endothelial cells. Pharmacological stabilization of β-catenin significantly rescued Brg1 mutant vessel morphology and transcription of Wnt target genes. Our data demonstrate that BRG1 impacts the canonical Wnt pathway at two different levels in vascular endothelium: through transcriptional regulation of both Wnt receptor genes and Wnt target genes. These findings establish an epigenetic mechanism for the modulation of Wnt signaling during embryonic vascular development.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. courtney-griffin@omrf.org
Courtney T
CT
Griffin
Carol D
CD
Curtis
Reema B
RB
Davis
Vijay
V
Muthukumar
Terry
T
Magnuson
D000818:Animals; D002460:Cell Line; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology; D044127:Epigenesis, Genetic / Q000502:physiology; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D051157:Frizzled Receptors; D009687:Nuclear Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
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