Identification and Functional Studies of Regulatory Variants Responsible for the Association of &lt;b&gt;&lt;i&gt;NRG3&lt;/i&gt;&lt;/b&gt; with a Delusion Phenotype in Schizophrenia

Zeledon, Mariela; Eckart, Nicole; Taub, Margaret A.; Vernon, Hilary J.; Szymanksi, Megan; Wang, Ruihua; Chen, Pei‐Lung; Nestadt, G.; McGrath, John A.; Sawa, Akira; Pulver, Ann E.; Avramopoulos, Dimitrios; Valle, David

doi:10.1159/000371518

Cited by 14 publications

(15 citation statements)

References 51 publications

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“…As noted in Table 2, NRG1 (discussed above) and NRG3 are commonly cited as candidates for both SZ and ASD (Kao et al 2010, Hatzimanolis et al 2013, Hou et al 2014, Tost et al 2014, Shen et al 2015, Yoo et al 2015, Zeledón et al 2015. Together with its receptor ERBB4 (also discussed above), NRG1 is involved in the enhancement of synchronized oscillations in the prefrontal cortex, known to be reduced in SZ (Fisahn et al 2009, Hou et al 2014.…”

Section: Common Candidates For Sz Asd and Language Evolution: A Funcmentioning

confidence: 96%

Language deficits in schizophrenia and autism as related oscillatory connectomopathies: an evolutionary account

Murphy

Benítez‐Burraco

2016

Preprint

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Schizophrenia (SZ) and autism spectrum disorders (ASD) are characterised by marked language deficits, but it is not clear how these arise from gene mutations associated with the disorders. Our goal is to narrow the gap between SZ and ASD and, ultimately, give support to the view that they represent abnormal (but related) ontogenetic itineraries for the human faculty of language. We will focus on the distinctive oscillatory profiles of the SZ and ASD brains, in turn using these insights to refine our understanding of how the brain computes language by exploring a novel model of linguistic feature-set composition. We will argue that brain rhythms constitute the best route to interpreting language deficits in both conditions and mapping them to neural dysfunction and risk alleles of the genes. Importantly, candidate genes for SZ and ASD are overrepresented among the gene sets believed to be important for language evolution. This translational effort may help develop an understanding of the aetiology of SZ and ASD and their high prevalence among modern populations.

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Section: Common Candidates For Sz Asd and Language Evolution: A Funcmentioning

confidence: 96%

Language deficits in schizophrenia and autism as related oscillatory connectomopathies: an evolutionary account

Murphy

Benítez‐Burraco

2016

Preprint

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“…Nrg2 resembles the Ig-like domain containing isoforms of Nrg1, a domain absent from Nrg3 isoforms. Little is known about the alternative splicing of Nrg3 in the rodent, in contrast to its detailed characterization in human (Carteron, Ferrer-Montiel, & Cabedo, 2006;Kao et al, 2010;Paterson et al, 2017;Zeledon et al, 2015). The Nrg3 human transcripts have been categorized into four major types, shown to be dynamically regulated throughout prefrontal cortical development (Paterson et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Developmental expression of Neuregulin‐3 in the rat central nervous system

Rahman

Weber

Labin

et al. 2018

J of Comparative Neurology

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Neuregulin‐3 (Nrg3) is a member of the Nrg family of growth factors identified as risk factors for schizophrenia. There are three Nrgs expressed in the nervous system (Nrg1‐3) and of these Nrg1 has been the best characterized. To set the groundwork for elucidating neural roles for Nrg3, we studied its expression in the rat brain at both the RNA and protein levels. Using an antibody developed against Nrg3, we observed a developmental increase of Nrg3 protein expression from embryonic stages to adulthood and determined that it carries O‐linked carbohydrates. In cortical neuronal cultures, transfected Neuro2a cells, and brain tissue sections Nrg3 protein was localized to the soma, neurites, and to the Golgi apparatus, where it is prominently expressed. Nrg3 was detected in excitatory, GABAergic and parvalbumin‐expressing inhibitory neurons while expression in glia was limited. Nrg3 mRNA and protein were widely expressed during both embryonic and postnatal ages. At E17, Nrg3 was detected within the cortical plate and ventricular zone suggesting possible roles in cell proliferation or migration. At postnatal ages, Nrg3 was abundantly expressed throughout the cerebral cortex and hippocampus. Multiple thalamic nuclei expressed Nrg3, while detection in the striatum was limited. In the cerebellum, Nrg3 was found in both Purkinje cells and granule neurons. In the rodent brain, Nrg3 is the most abundantly expressed of the Nrgs and its patterns of expression differ both temporally and spatially from that of Nrg1 and Nrg2. These findings suggest that Nrg3 plays roles that are distinct from the other Nrg family members.

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“…Similar to NRG1, NRG3 undergoes complex alternative splicing and promoter use, generating at least 15 alternative transcripts (7, 13, 18). Our recent cloning of the gene and transcriptional studies in human brain characterized these isoforms into four “classes” based on exon homology, termed NRG3 classes I–IV (7).…”

mentioning

confidence: 99%

“…While the mechanistic role of rs10748842 remains to be determined, bioinformatics analyses identify the SNP as central to an ultraconserved genomic element and homeo-domain binding module that modifies transcription factor binding (7, 18). In the human brain, the risk allele (T) is associated with increased prefrontal cortical expression of NRG3 classes II and III in patients with schizophrenia, nonpsychiatric adult control subjects, and the fetal neocortex, highlighting a potential molecular mechanism of risk (7, 18).…”

mentioning

confidence: 99%

“…In the human brain, the risk allele (T) is associated with increased prefrontal cortical expression of NRG3 classes II and III in patients with schizophrenia, nonpsychiatric adult control subjects, and the fetal neocortex, highlighting a potential molecular mechanism of risk (7, 18). Furthermore, classes I and IV are significantly increased in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients compared with nonpsychiatric control subjects (7).…”

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confidence: 99%

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Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

Paterson

Wang

Hyde

et al. 2017

AJP

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Objective Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I–IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. Method NRG3 isoform classes I–IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. Results NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Conclusions Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment developme...

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Identification and Functional Studies of Regulatory Variants Responsible for the Association of <b><i>NRG3</i></b> with a Delusion Phenotype in Schizophrenia

Cited by 14 publications

References 51 publications

Language deficits in schizophrenia and autism as related oscillatory connectomopathies: an evolutionary account

Language deficits in schizophrenia and autism as related oscillatory connectomopathies: an evolutionary account

Developmental expression of Neuregulin‐3 in the rat central nervous system

Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

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