title: Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons.
abstract: De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin-Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability.
  
  
  CONCLUSIONS
  Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons.
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198, and.
authors.forename: Minhan
authors.initials: M
authors.lastname: Ka
authors.affiliation: Department of Pharmacology, Creighton University, Omaha, Nebraska 68178.
authors.forename: Divyan A
authors.initials: DA
authors.lastname: Chopra
authors.affiliation: Department of Pharmacology, Creighton University, Omaha, Nebraska 68178.
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198, and wooyang.kim@unmc.edu.
authors.forename: Woo-Yang
authors.initials: WY
authors.lastname: Kim
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology* / Q000254:growth & development*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017966:Pyramidal Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins
keywords: ARID1B; chromatin remodeling complex; dendrite arborization; intellectual disability; spine