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Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure

Deans, P.J. Michael, Raval, Pooja, Sellers, Katherine J., Gatford, Nicholas J.F., Halai, Sanjay, Duarte, Rodrigo R.R., Shum, Carole, Warre-Cornish, Katherine, Kaplun, Victoria E., Cocks, Graham, Hill, Matthew, Bray, Nicholas, Price, Jack and Srivastava, Deepak P. 2017. Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure. Biological psychiatry 82 (1) , pp. 49-61. 10.1016/j.biopsych.2016.08.038

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Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled 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
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 21 November 2016
Date of Acceptance: 22 August 2016
Last Modified: 30 Apr 2019 12:42
URI: http://orca-mwe.cf.ac.uk/id/eprint/96301

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