title: Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling.
abstract: Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zilai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mou
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Chang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xuanming
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA jiang9.wu@utsouthwestern.edu.
authors.forename: Jiang I
authors.initials: JI
authors.lastname: Wu
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D064326:MEF2 Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases