Genetic Evidence for the Association between the Early Growth Response 3 (EGR3) Gene and Schizophrenia

Zhang, Rui; Lu, Shemin; Li, Meng; Min, Zixin; Tian, Juan; Valenzuela, Robert K.; Guo, Tingwei; Tian, Liang; Zhao, Wenxiang; Ma, Jie

doi:10.1371/journal.pone.0030237

Cited by 24 publications

(26 citation statements)

References 62 publications

(98 reference statements)

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“…36 Human genetic studies further support a role for EGR3 in this mental illness, as variations in the EGR3 gene have been associated with schizophrenia in three populations. 19–21 Post-mortem studies have also shown decreased levels of EGR3 expression in the brains of schizophrenia patients. 20, 37 Animal studies show that mice lacking Egr3 display schizophrenia-like abnormal behaviors, such as increased locomotion, aggression and deficits in memory and synaptic plasticity.…”

Section: Resultsmentioning

confidence: 99%

Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner

Maple

Zhao

Elizalde

et al. 2015

ACS Chem. Neurosci.

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Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical Htr2a mRNA in mice. We found that 6 hours of sleep deprivation induces a 2-fold increase in Htr2a mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (Egr3), as sleep deprivation failed to induce Htr2a expression in Egr3−/− mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner

Maple

Zhao

Elizalde

et al. 2015

ACS Chem. Neurosci.

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“…Such disrupted genes were relevant to neurological diseases, including systemic lupus erythematosus (SLE; table 4). Xbp1 and Egr3 have been previously associated with schizophrenia given their roles in unfolded protein response in neurons and in neuromuscular synaptic transmission, respectively [47,48]. A number of genes were also involved in endoplasmic reticulum (ER) stress response.…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes during Neurodevelopment following Second-Trimester Binge Ethanol Exposure in a Mouse Model of Fetal Alcohol Spectrum Disorder: From Immediate Effects to Long-Term Adaptation

Mantha

Laufer

Singh³

2014

Dev Neurosci

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Fetal alcohol spectrum disorder (FASD) is an umbrella term that refers to a wide range of behavioral and cognitive deficits resulting from prenatal alcohol exposure. It involves changes in brain gene expression that underlie lifelong FASD symptoms. How these changes are achieved from immediate to long-term effects, and how they are maintained, is unknown. We have used the C57BL/6J mouse to assess the dynamics of genomic alterations following binge alcohol exposure. Ethanol-exposed fetal (short-term effect) and adult (long-term effect) brains were assessed for gene expression and microRNA (miRNA) changes using Affymetrix mouse arrays. We identified 48 and 68 differentially expressed genes in short- and long-term groups, respectively. No gene was common between the 2 groups. Short-term (immediate) genes were involved in cellular compromise and apoptosis, which represent ethanol's toxic effects. Long-term genes were involved in various cellular functions, including epigenetics. Using quantitative RT-PCR, we confirmed the downregulation of long-term genes: Camk1g, Ccdc6, Egr3, Hspa5, and Xbp1. miRNA arrays identified 20 differentially expressed miRNAs, one of which (miR-302c) was confirmed. miR-302c was involved in an inverse relationship with Ccdc6. A network-based model involving altered genes illustrates the importance of cellular redox, stress and inflammation in FASD. Our results also support a critical role of apoptosis in FASD, and the potential involvement of miRNAs in the adaptation of gene expression following prenatal ethanol exposure. The ultimate molecular footprint involves inflammatory disease, neurological disease and skeletal and muscular disorders as major alterations in FASD. At the cellular level, these processes represent abnormalities in redox, stress and inflammation, with potential underpinnings to anxiety.

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“…Another gene that has been implicated in both SZ and circadian organization is immediate early gene growth response 3 (Egr3) 162,[165][166][167][168] . Additional support for this candidate gene is provided by Egr3-deficient mice (−/−), which display behaviors that are reminiscent of SZ and sleep less than WT controls, even though the circadian organization of the sleep-wake cycle remained intact 169 .…”

Section: Circadian Rhythm Disruption and Schizophreniamentioning

confidence: 99%

Circadian rhythm disruption and mental health

et al. 2020

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Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light-dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

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Genetic Evidence for the Association between the Early Growth Response 3 (EGR3) Gene and Schizophrenia

Cited by 24 publications

References 62 publications

Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner

Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner

Molecular Changes during Neurodevelopment following Second-Trimester Binge Ethanol Exposure in a Mouse Model of Fetal Alcohol Spectrum Disorder: From Immediate Effects to Long-Term Adaptation

Circadian rhythm disruption and mental health

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