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PMID:23319608

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Citation

Li, W, Xiong, Y, Shang, C, Twu, KY, Hang, CT, Yang, J, Han, P, Lin, CY, Lin, CJ, Tsai, FC, Stankunas, K, Meyer, T, Bernstein, D, Pan, M and Chang, CP (2013) Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development. Proc. Natl. Acad. Sci. U.S.A. 110:1738-43

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.

Links

PubMed PMC3562770 Online version:10.1073/pnas.1218072110

Keywords

Animals; Apoptosis/genetics; Cardiovascular System/cytology; Cardiovascular System/embryology; Cardiovascular System/metabolism; Cell Movement/genetics; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/metabolism; DNA Helicases/genetics; DNA Helicases/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Embryo, Mammalian/blood supply; Embryo, Mammalian/cytology; Embryo, Mammalian/embryology; Female; Gene Expression Regulation, Developmental; In Situ Hybridization; MAP Kinase Kinase Kinase 5/genetics; MAP Kinase Kinase Kinase 5/metabolism; Mice; Microscopy, Fluorescence; Multipotent Stem Cells/metabolism; Mutation; Myosin Heavy Chains/genetics; Myosin Heavy Chains/metabolism; Neural Crest/cytology; Neural Crest/embryology; Neural Crest/metabolism; Neural Stem Cells/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Pregnancy; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/genetics; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CHD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P70207

F

Seeded From UniProt

complete

MOUSE:CHD7

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMCA4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:A2AJK6

F

Seeded From UniProt

complete

MOUSE:SMCA4

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0061626: pharyngeal arch artery morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0045597: positive regulation of cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

MOUSE:SMCA4

acts_upstream_of_or_within

GO:0030334: regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3605892

P

Seeded From UniProt

complete

Notes

See also

References

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