title: The SWI/SNF BAF-A complex is essential for neural crest development.
abstract: Growing evidence indicates that chromatin remodeler mutations underlie the pathogenesis of human neurocristopathies or disorders that affect neural crest cells (NCCs). However, causal relationships among chromatin remodeler subunit mutations and NCC defects remain poorly understood. Here we show that homozygous loss of ARID1A-containing, SWI/SNF chromatin remodeling complexes (BAF-A) in NCCs results in embryonic lethality in mice, with mutant embryos succumbing to heart defects. Strikingly, monoallelic loss of ARID1A in NCCs led to craniofacial defects in adult mice, including shortened snouts and low set ears, and these defects were more pronounced following homozygous loss of ARID1A, with the ventral cranial bones being greatly reduced in size. Early NCC specification and expression of the BRG1 NCC target gene, PLEXINA2, occurred normally in the absence of ARID1A. Nonetheless, mutant embryos displayed incomplete conotruncal septation of the cardiac outflow tract and defects in the posterior pharyngeal arteries, culminating in persistent truncus arteriosus and agenesis of the ductus arteriosus. Consistent with this, migrating cardiac NCCs underwent apoptosis within the circumpharyngeal ridge. Our data support the notion that multiple, distinct chromatin remodeling complexes govern genetically separable events in NCC development and highlight a potential pathogenic role for NCCs in the human BAF complex disorder, Coffin-Siris Syndrome.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, United States.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Chandler
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, United States. Electronic address: trm4@med.unc.edu.
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005145:Face / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D006228:Hand Deformities, Congenital / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D008844:Micrognathism / Q000235:genetics; D009333:Neck / Q000002:abnormalities; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009432:Neural Crest / Q000166:cytology / Q000196:embryology*; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C511511:Arid1a protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C492113:Plxna2 protein, mouse; D011956:Receptors, Cell Surface; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors
keywords: ARID1A; BAF-A; Coffin-Siris syndrome; Neural crest; SWI/SNF