title: Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development.
abstract: Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21(cip1), to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.
authors: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Wei
authors: W
authors: Li
authors: Yiqin
authors: Y
authors: Xiong
authors: Ching
authors: C
authors: Shang
authors: Karen Y
authors: KY
authors: Twu
authors: Calvin T
authors: CT
authors: Hang
authors: Jin
authors: J
authors: Yang
authors: Pei
authors: P
authors: Han
authors: Chieh-Yu
authors: CY
authors: Lin
authors: Chien-Jung
authors: CJ
authors: Lin
authors: Feng-Chiao
authors: FC
authors: Tsai
authors: Kryn
authors: K
authors: Stankunas
authors: Tobias
authors: T
authors: Meyer
authors: Daniel
authors: D
authors: Bernstein
authors: Minggui
authors: M
authors: Pan
authors: Ching-Pin
authors: CP
authors: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002319:Cardiovascular System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D039902:Multipotent Stem Cells / Q000378:metabolism*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; C507367:Chd7 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C573943:myosin 11, mouse; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; D018995:Myosin Heavy Chains