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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Cardiovascular System / cytology
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Cardiovascular System / embryology
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Cardiovascular System / metabolism
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Cell Movement / genetics
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Cell Proliferation
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / blood supply
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Embryo, Mammalian / cytology
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Embryo, Mammalian / embryology
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Female
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Gene Expression Regulation, Developmental
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In Situ Hybridization
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism
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Mice
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Microscopy, Fluorescence
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Multipotent Stem Cells / metabolism*
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Mutation
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Myosin Heavy Chains / genetics
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Myosin Heavy Chains / metabolism
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Neural Crest / cytology
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Neural Crest / embryology
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Neural Crest / metabolism
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Neural Stem Cells / metabolism*
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Pregnancy
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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Cdkn1a protein, mouse
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Chd7 protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Nuclear Proteins
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Transcription Factors
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myosin 11, mouse
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MAP Kinase Kinase Kinase 5
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Map3k5 protein, mouse
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Smarca4 protein, mouse
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DNA Helicases
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Myosin Heavy Chains