The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation

Abstract

Early growth response 3 (Egr3) is an immediate early gene (IEG) that is regulated downstream of a cascade of genes associated with risk for psychiatric disorders, and dysfunction of Egr3 itself has been implicated in schizophrenia, bipolar disorder, and depression. As an activity-dependent transcription factor, EGR3 is poised to regulate the neuronal expression of target genes in response to environmental events. In the current study, we sought to identify a downstream target of EGR3 with the goal of further elucidating genes in this biological pathway relevant for psychiatric illness risk. We used electroconvulsive stimulation (ECS) to induce high-level expression of IEGs in the brain, and conducted expression microarray to identify genes differentially regulated in the hippocampus of Egr3-deficient (-/-) mice compared to their wildtype (WT) littermates. Our results replicated previous work showing that ECS induces high-level expression of the brain-derived neurotrophic factor (Bdnf) in the hippocampus of WT mice. However, we found that this induction is absent in Egr3-/- mice. Quantitative real-time PCR (qRT-PCR) validated the microarray results (performed in males) and replicated the findings in two separate cohorts of female mice. Follow-up studies of activity-dependent Bdnf exons demonstrated that ECS-induced expression of both exons IV and VI requires Egr3. In situ hybridization demonstrated high-level cellular expression of Bdnf in the hippocampal dentate gyrus following ECS in WT, but not Egr3-/-, mice. Bdnf promoter analysis revealed eight putative EGR3 binding sites in the Bdnf promoter, suggesting a mechanism through which EGR3 may directly regulate Bdnf gene expression. These findings do not appear to result from a defect in the development of hippocampal neurons in Egr3-/- mice, as cell counts in tissue sections stained with anti-NeuN antibodies, a neuron-specific marker, did not differ between Egr3-/- and WT mice. In addition, Sholl analysis and counts of dendritic spines in golgi-stained hippocampal sections revealed no difference in dendritic morphology or synaptic spine density in Egr3-/-, compared to WT, mice. These findings indicate that Egr3 is required for ECS-induced expression of Bdnf in the hippocampus and suggest that Bdnf may be a downstream gene in our previously identified biologically pathway for psychiatric illness susceptibility.

Single-cell gene regulatory network analysis reveals new melanoma cell states and transition trajectories during phenotype switching

“…Interestingly, these transcription factors have been implicated in mechanisms that could explain the intermediate cell state's characteristics. EGR3, as a member of the early growth response genes, is needed for the induction of important cellular programs such as neurogenesis (Kim et al 2012;Quach et al 2013;Meyers et al 2018), inflammation and the immune response (S. Li et al 2012;Baron et al 2015), VEGF-mediated angiogenesis (Liu Dan et al 2003;Kang et al 2014) and the maintenance of stemness (Hamra et al 2004). In line with these observations, gene set enrichment analysis (GSEA) of the SCENIC-predicted EGR3 target genes shows enrichment of gene signatures characteristic for vasculature development and stem cells.…”

Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport

“…Early growth response 3 (EGR3) regulates the expression of about 330 genes, 35% of which are involved in immune responses and inflammatory processes, and 15% crosstalk with the NF-κB signaling pathway [133]. It also regulates genes involved in synaptic plasticity, memory, and cognition [134] and has been associated with schizophrenia, bipolar disorder, and depression [135]. Binding sites for NF-kB, which play a key role in inflammatory processes, are present also in the promoter region of adhesion molecules, cytokines, and growth factors [136].…”

miR‑454‑3p promotes of human glioma cell growth by targeting EGR3

“…Overexpression of EGR3 was also found to reverse miR-454-3p mimic-induced cell proliferation in vitro . Previous studies reported that EGR3 was ubiquitously expressed in the cerebral cortex, substrate ganglion and neuromuscular spindle (13). Increased EGR3 expression induced expression of IL-6 and IL-8 has been previously demonstrated in prostate cancer (29), suggesting that EGR3 also serves an important role in tumorigenesis.…”

“…Early growth response 3 (EGR3) is a member of the EGR family of C2H2-type zinc-finger proteins (13). It regulates gene transcription and has been found to be involved in multiple biological processes, including the development of muscle, lymphocyte and neurons, in addition to the growth, migration, invasion and metastasis of cancer cells (14–16).…”