title: A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice.
abstract: Failure of embryonic neural tube closure results in the second most common class of birth defects known as neural tube defects (NTDs). While NTDs are likely the result of complex multigenic dysfunction, it is not known whether polymorphisms in epigenetic regulators may be risk factors for NTDs. Here we characterized Baf155(msp3) , a unique ENU-induced allele in mice. Homozygous Baf155(mps3) embryos exhibit highly penetrant exencephaly, allowing us to investigate the roles of an assembled, but malfunctional BAF chromatin remodeling complex in vivo at the time of neural tube closure. Evidence of defects in proliferation and apoptosis were found within the neural tube. RNA-Seq analysis revealed that surprisingly few genes showed altered expression in Baf155 mutant neural tissue, given the broad epigenetic role of the BAF complex, but included genes involved in neural development and cell survival. Moreover, gene expression changes between individual mutants were variable even though the NTD was consistently observed. This suggests that inconsistent gene regulation contributes to failed neural tube closure. These results shed light on the role of the BAF complex in the process of neural tube closure and highlight the importance of studying missense alleles to understand epigenetic regulation during critical phases of development.
authors.affiliation: Department of Pediatrics and Graduate Program in Molecular Biology, Howard Hughes Medical Institute, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado, 80045.
authors.forename: Laura
authors.initials: L
authors.lastname: Harmacek
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Watkins-Chow
authors.forename: Jianfu
authors.initials: J
authors.lastname: Chen
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: J Michael
authors.initials: JM
authors.lastname: Salbaum
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D060005:Genotyping Techniques; D047468:Immunoprecipitation; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020125:Mutation, Missense; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D054259:Neural Tube / Q000378:metabolism / Q000473:pathology; D009436:Neural Tube Defects / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C491090:Smarcc1 protein, mouse; D014157:Transcription Factors
keywords: Baf155msp3; apoptosis; epigenetic regulation; neural tube defect; proliferation