Abstract
BackgroundVariation 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. MethodsThe 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. ResultsEndogenous 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. ConclusionsThese 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.
Highlights
Variation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia and bipolar disorder
Whereas functional studies suggest that ZNF804A controls the expression of genes involved in cell adhesion, neurite outgrowth, and synaptic transmission [15,19], little is known about the cellular function of this susceptibility gene
We present evidence that ZNF804A/Zfp804a localizes to dendrites and synapses, in both neurons derived from either human neural progenitor cells (hNPCs) or hiPSC sources and mature rat cortical neurons. small interfering RNA (siRNA)-mediated loss of ZNF804A further reveals a role in establishing early neuronal morphology, an effect potentially mediated by the ability of ZNF804A to regulate the expression of the adhesion protein NLGN4, a protein implicated in autism spectrum disorders (ASDs) [21,22]
Summary
Variation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia and bipolar disorder. These data reveal a novel subcellular distribution for ZNF804A/Zfp8084A as well as determining a functional role in the formation of early neuronal morphology and the regulation of excitatory synapses. Expressed myc-ZNF804A in early stage CTX0E16 neurons localized along double cortin-positive neurites further supporting an extranuclear distribution in neurons (Supplemental Figure S4C).
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