Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging

Jenkins, Aaron; Paterson, Clare; Wang, Yanhong; Hyde, Thomas M.; Kleinman, Joel E.; Law, Amanda J.

doi:10.1038/mp.2015.107

Cited by 53 publications

(43 citation statements)

References 50 publications

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“…NRXN1 has been implicated in neocortical development and aging [23], and NRXN1 genetic variations affect the risk of autism and schizophrenia [28, 29]. Of note, we reported the locus including NRXN1 already in our previous work highlighting novel suggestive loci for FTD in the Italian population [3]; here, we provide further support for this association and expand on its potential implication in driving AAO.…”

Section: Discussionsupporting

confidence: 80%

“…Considering the 6 loci that we identified influencing AAO in FTD, the literature suggests, particularly for NRXN, HPCAL1 , and PTPRD , a direct link with the biology of the brain through calcium-mediated neuronal signaling, development of neocortical regions as well as axonal myelination and glutamatergic/GABAergic synapsis, respectively [23–26]. It is interesting to gather that variability in these genes, and their associated functions and processes, could underpin the modulation of disease onset in FTD.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Ferrari¹,

Grassi

Graziano

et al. 2017

JAD

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In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by −3.86 (95%CI: −4.64 to −3.07, p < 2 × 10−16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Ferrari¹,

Grassi

Graziano

et al. 2017

JAD

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“…Furthermore, transcripts of these 108 genes show elevated expression patterns in fetal brain when compared to post-natal brain [16]. Similar studies have reported increased expression of schizophrenia risk genes during early brain development [17, 18]. These findings are consistent with a generalized neurodevelopmental role for many genes associated with risk of schizophrenia.…”

Section: Genetics and Epigenetics Of Schizophreniasupporting

confidence: 78%

Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches

et al. 2019

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Schizophrenia is a chronic mental disorder that is still poorly understood despite decades of study. Many factors have been found to contribute to the pathogenesis, including neurodevelopmental disturbance, genetic risk, and environmental insult, but no single root cause has emerged. While evidence from twin studies suggests a strong heritable component, few individual loci have been identified in genomewide screens, suggesting a role for epigenetic effects. Rather, large numbers of weakly acting loci may cumulatively increase disease risk, including several mapping to epigenetic pathways. In this review, we discuss mechanisms of epigenetic regulation and evidence for an epigenetic contribution to disease phenotype. We further describe the range of experimental tools currently available to study epigenetic effects associated with the disease.

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“…Full details of the postmortem human brain collection used in the current study have been previously described (25). Additional information regarding tissue collection is provided in the data supplement accompanying the online version of this article.…”

Section: Methodsmentioning

confidence: 99%

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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Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging

Cited by 53 publications

References 50 publications

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches

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

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