Abstract
Schizophrenia (SZ) is a devastating brain disease that affects 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 development. 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 attenuate dendritic complex and spine formation. To determine the factors 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, LGALS1 but not FEZ1, reverses the neurite outgrowth deficits induced by ZNF804A knockdown. However, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A overexpression-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant to neurodevelopmental pathologies.
Highlights
In 2008, O’Donovan and colleagues identified the zinc finger protein 804A (ZNF804A) as the first gene to reach the genome-wide significance associated with SZ [1]
ZNF804A knockdown affects the neurite outgrowth and spine formation ZNF804A protein is enriched in neurites (Fig. 1a, g, i) and we have identified a group of ZNF804A interacting proteins involved in the neurite outgrowth using yeast2-hybrid system (Y2H) [8] including fasciculation and elongation protein zeta 1 (FEZ1) and Galectin 1 (LGALS1)
ZNF804A is highly expressed in neural progenitors (NPs) and reaches a peak at E14 in the embryonic mouse brain [8]
Summary
In 2008, O’Donovan and colleagues identified the ZNF804A as the first gene to reach the genome-wide significance associated with SZ [1]. The associations between ZNF804A and SZ were confirmed by other groups [2,3,4]. Besides single nucleotide polymorphisms (SNPs), CNVs of ZNF804A have been reported in patients with psychiatric diseases [3]. ZNF804A CNVs, including duplication and deletion, were observed in patients with ASDs [6], supporting that ZNF804A risk is limited to SZ. These results suggest that ZNF804A dosage is critical and altered expression may lead to various developmental disorders
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