Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia

Abstract

Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer’s disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice. To identify Egr3-dependent genes that may regulate these processes, we conducted an expression microarray on hippocampi from wildtype (WT) and Egr3−/− mice following electroconvulsive seizure (ECS), a stimulus that induces maximal expression of immediate early genes including Egr3. We identified 69 genes that were differentially expressed between WT and Egr3−/− mice one hour following ECS. Bioinformatic analyses showed that many of these are altered in, or associated with, schizophrenia, including Mef2c and Calb2. Enrichr pathway analysis revealed the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g) as a leading group of differentially expressed genes. Together with differentially expressed genes in the AP-1 transcription factor family genes (Fos, Fosb), and the centromere organization protein Cenpa, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the DNA damage response. Our findings show that EGR3 is critical for the expression of genes that are mis-expressed in schizophrenia and reveal a novel requirement for EGR3 in the expression of genes involved in activity-induced DNA damage response.

egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis

“…3, B and C ) ( 49 , 50 ). Our observations that nr4a2b and spp1 are down-regulated in egr3 mutants agree with published reports in mammals showing that EGR3 is upstream of Nr4a2 ( 51 ) and that NR4A2 activates SPP1 expression by binding to its promoter ( 52 ). Moreover, EGR3 ( 53 , 54 ), NR4A2 ( 55 ), and SPP1 ( 56 , 57 ) promote endothelial cell migration downstream of vascular endothelial growth factor (VEGF), supporting the model that Egr3 is necessary for EdC migration during valvulogenesis.…”

Transposons contribute to the acquisition of cell type-specific cis-elements in the brain

“…To check to what extent the candidate transcription factor genes are actively transcribed in the cell types where the de novo motifs are accessible, we examined their RNA expression levels using public scRNA-seq data of the adult mouse cortex 13 and gene activity levels using scATAC-seq data 33 (see “Methods”). We confirmed that specific transcription factors of the candidates that regulate neural differentiation and/or neuronal activity are highly expressed in each cell population 7 , 8 , 37 – 40 (Fig. 2 d, Supplementary Fig.…”

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

“…In the present study, we uncover a novel C1ql2-dependent regulatory pathway through which Bcl11b controls the structural as well as functional integrity of hippocampal MFS in adult mice. We show that SV recruitment to the AZ of MFS, as well as the expression of MF-LTP, depend on C1ql2, which is a direct functional target of Recent studies suggested Nrxn3, as well as C1ql2, to be associated with neuropsychiatric disorders (Hishimoto et al, 2007;Hu et al, 2013;Huggett & Stallings, 2020a, 2020bMarballi et al, 2022). Our study for the first time identifies a Bcl11b/C1ql2/Nrxn3-dependent signaling pathway in the control of basic structural and functional properties of MFS.…”

“…Finally, we show that C1ql2 controls SV recruitment through a direct interaction with presynaptic Nrxn3(25b+), while LTP depends on C1ql2 signals independent of Nrxn3 interaction. Recent studies suggested Nrxn3, as well as C1ql2, to be associated with neuropsychiatric disorders (Hishimoto et al, 2007; Hu et al, 2013; Huggett & Stallings, 2020a, 2020b; Marballi et al, 2022). Our study for the first time identifies a Bcl11b/C1ql2/Nrxn3-dependent signaling pathway in the control of basic structural and functional properties of MFS.…”

“…NRXN3 single-nucleotide polymorphisms (SNP) have been implicated in schizophrenia (Hu et al, 2013) and addiction (Hishimoto et al, 2007), with one recorded SNP located close to SS5 altering the expression of Nrxn3(25b+). Interestingly, recent studies have also associated C1QL2 with schizophrenia (Marballi et al, 2022) as well as cocaine addiction (Huggett & Stallings, 2020a, 2020b). In this study we demonstrate that Bcl11b, through its transcriptional target C1ql2, modulates the synaptic organization of MFS by controlling the recruitment of SV at AZ.…”