Schizophrenia Risk ZNF804A Interacts with its Associated Proteins to Modulate Dendritic Morphology and Synaptic Development

Abstract

Schizophrenia (SZ) is a devastating brain disease that affect about 1% of world population. Among the top genetic associations, zinc finger protein 804A (ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) of ZNF804A have been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting that ZNF804A is a dosage sensitive gene for brain function. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage of ZNF804A on neurite morphology, both knockdown and overexpression of ZNF804A in primary neuronal cells significantly attenuates dendritic morphology and synaptogenesis. To determine the effectors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant for neurodevelopmental pathologies.

FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migration

“…2E, upper panel; Table S2). These results correlated well with the established function of FEZ1 in neuronal development and synaptic function (Butkevich et al, 2016; Chua et al, 2021; Dong et al, 2021; Gunaseelan et al, 2021; Kang et al, 2011). Genes upregulated in the absence of FEZ1 were primarily associated with Wnt signaling, sensory system development, tyrosine metabolism and semaphorin interactions (Fig.…”

“…2E, upper panel; Table S2). These results correlated well with the established function of FEZ1 in neuronal development and synaptic function (Butkevich et al, 2016;Chua et al, 2021;Dong et al, 2021;Gunaseelan et al, 2021;Kang et al, 2011).…”

Single-cell multi-cohort dissection of the schizophrenia transcriptome

“…SOX5 is implicated in fate determination and regulation of corticofugal projection neuron development, with loss-of-function perturbations leading to disrupted neuronal proportions and emergence timing (59). ZNF804A is a schizophrenia fine-mapping prioritized GWAS gene (15) involved in neurodevelopment, synapse development, and dendritic morphology (60).…”

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation

“…SNP rs1344704 is located in the second intron of the ZNF804A gene, being the first to show a significant association with increased susceptibility to schizophrenia in a GWAS (O'Donovan et al, 2008), which has been consistently replicated in larger subsequent ones (Ripke et al, 2014; Steinberg et al, 2011; Williams et al, 2011), also extending to bipolar disorder, mainly in the context of European populations. ZNF804A is known to be highly expressed in brain tissues, specifically in the cytoplasm, neurites and dendritic spines in the human cortex (with higher density in the cingulate cortex), as well as in various types of mouse neurons (including pyramidal, dopaminergic and glutamatergic ones) (Dong, Mao, Chen, Yoon, & Mao, 2021).…”