title: Psychosis Risk Candidate ZNF804A Localizes to Synapses and Regulates Neurite Formation and Dendritic Spine Structure.
abstract: Variation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia and bipolar disorder. Evidence suggests that ZNF804A is a regulator of gene transcription and is present in nuclear and extranuclear compartments. However, a detailed examination of ZNF804A distribution and its neuronal functions has yet to be performed.
  
  
  
  The localization of ZNF804A protein was examined in neurons derived from human neural progenitor cells, human induced pluripotent stem cells, or in primary rat cortical neurons. In addition, small interfering RNA-mediated knockdown of ZNF804A was conducted to determine its role in neurite formation, maintenance of dendritic spine morphology, and responses to activity-dependent stimulations.
  
  
  
  Endogenous ZNF804A protein localized to somatodendritic compartments and colocalized with the putative synaptic markers in young neurons derived from human neural progenitor cells and human induced pluripotent stem cells. In mature rat neurons, Zfp804A, the homolog of ZNF804A, was present in a subset of dendritic spines and colocalized with synaptic proteins in specific nanodomains, as determined by super-resolution microscopy. Interestingly, knockdown of ZNF804A attenuated neurite outgrowth in young neurons, an effect potentially mediated by reduced neuroligin-4 expression. Furthermore, knockdown of ZNF804A in mature neurons resulted in the loss of dendritic spine density and impaired responses to activity-dependent stimulation.
  
  
  
  These data reveal a novel subcellular distribution for ZNF804A within somatodendritic compartments and a nanoscopic organization at excitatory synapses. Moreover, our results suggest that ZNF804A plays an active role in neurite formation, maintenance of dendritic spines, and activity-dependent structural plasticity.
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: P J Michael
authors.initials: PJM
authors.lastname: Deans
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Pooja
authors.initials: P
authors.lastname: Raval
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Sellers
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Nicholas J F
authors.initials: NJF
authors.lastname: Gatford
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Halai
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Rodrigo R R
authors.initials: RRR
authors.lastname: Duarte
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Carole
authors.initials: C
authors.lastname: Shum
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Katherine
authors.initials: K
authors.lastname: Warre-Cornish
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Kaplun
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London.
authors.forename: Graham
authors.initials: G
authors.lastname: Cocks
authors.affiliation: MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, United Kingdom; Neuroscience and Mental Health Research Institute, College of Biomedical and Life Sciences, Cardiff University School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hill
authors.affiliation: MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London; United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Price
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London; United Kingdom.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Srivastava
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D011618:Psychotic Disorders / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; C540527:ZNF804A protein, human
keywords: Autism spectrum disorder; Bipolar disorder; Dendritic spine; GluN1; Human neurons; Induced pluripotent stem cells (iPSCs); Neural progenitor cells; PSD-95; Psychosis; Schizophrenia; Super-resolution microscopy; Synapse