Fernandez-Cuesta L and Thomas RK, Clin Cancer Res. 2015 May 1;21(9):1989-94. doi: 10.1158/1078-0432.CCR-14-0854. Epub 2014 Dec 11.
The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand-receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1
ont-weight:700;'>NRG1, which represent a novel mechanism for ERBB pathway deregulation. These fusions lead to expression and presentation of the EGF-like domain of NRG1 on the cell surface, which binds to ERBB3 in an autocrine and juxtacrine manner, thus inducing the formation of ERBB2-ERBB3 heterodimers, and subsequent activation of the PI3K-AKT and MAPK signaling pathways. These fusion genes were exclusively detected in lung adenocarcinomas of never smokers of the invasive mucinous subtype, which usually presents as a multifocal and unresectable disease, for which no effective treatment exists. Considering the large amount of drugs that target ERBB2 (HER2) and ERBB3 (HER3), and which are currently in different stages of clinical development, detecting and targeting NRG1 fusions in invasive mucinous lung adenocarcinomas may represent a therapeutic opportunity for this aggressive disease.
The purpose of the present study was to investigate the possible association between temporal lobe epilepsy and NRG1 gene polymorphisms. A total of 73 patients and 69 controls were involved in this study. Genomic DNAs from the patients and controls were genotype
d by polymerase chain reaction-ligase detection reaction method. There was an association of rs35753505 (T>C) with temporal lobe epilepsy (chi(2) = 6.730, P = .035). The frequency of risk allele C of rs35753505 was significantly higher (69.9%) in patients compared to controls (55.8%) (chi(2) = 6.023, P = .014). Interestingly, the significant difference of NRG1 genotype and allele frequency only existed among males, but not females. In addition, no statistically significant association was found between rs6994992, rs62510682 polymorphisms, and temporal lobe epilepsy. These data indicate that rs35753505 of NRG1 plays an important role in conferring susceptibility to the temporal lobe epilepsy in a Chinese Han population.
Fleming MS, etal., J Neurosci. 2016 Oct 5;36(40):10337-10355.
Axon-Schwann cell interactions are crucial for the development, function, and repair of the peripheral nervous system, but mechanisms underlying communication between axons and nonmyelinating Schwann cells are unclear. Here, we show that ER81 is functionally required in a subset of mouse RET(+) mech
anosensory neurons for formation of Pacinian corpuscles, which are composed of a single myelinated axon and multiple layers of nonmyelinating Schwann cells, and Ret is required for the maintenance of Er81 expression. Interestingly, Er81 mutants have normal myelination but exhibit deficient interactions between axons and corpuscle-forming nonmyelinating Schwann cells. Finally, ablating Neuregulin-1 (Nrg1) in mechanosensory neurons results in no Pacinian corpuscles, and an Nrg1 isoform not required for communication with myelinating Schwann cells is specifically decreased in Er81-null somatosensory neurons. Collectively, our results suggest that a RET-ER81-NRG1 signaling pathway promotes axon communication with nonmyelinating Schwann cells, and that neurons use distinct mechanisms to interact with different types of Schwann cells. SIGNIFICANCE STATEMENT: Communication between neurons and Schwann cells is critical for development, normal function, and regeneration of the peripheral nervous system. Despite many studies about axonal communication with myelinating Schwann cells, mostly via a specific isoform of Neuregulin1, the molecular nature of axonal communication with nonmyelinating Schwann cells is poorly understood. Here, we described a RET-ER81-Neuregulin1 signaling pathway in neurons innervating Pacinian corpuscle somatosensory end organs, which is essential for communication between the innervating axon and the end organ nonmyelinating Schwann cells. We also showed that this signaling pathway uses isoforms of Neuregulin1 that are not involved in myelination, providing evidence that neurons use different isoforms of Neuregulin1 to interact with different types of Schwann cells.
Jung Y, etal., J Thorac Oncol. 2015 Jul;10(7):1107-11. doi: 10.1097/JTO.0000000000000544.
INTRODUCTION: Neuregulin 1 (NRG1) has been discovered as the tail moiety of fusion genes with several distinct partner head genes in lung cancers. These fusion genes activate ERBB2/ERBB3 receptor-mediated cell signaling and thereby function as oncogenic drivers.
METHODS: We have carried out whole-transcriptome sequencing of 100 non-small-cell lung carcinoma tumors and isolated a novel fusion gene consisting of vesicle-associated membrane protein 2 (VAMP2) and NRG1. Reverse transcription-polymerase chain reaction and genomic DNA analysis were used to demonstrate interchromosomal translocation. Immunoblotting and soft agar assays were used to examine stimulating activity of the fusion gene through ERBB2/ERBB3 signaling pathway. RESULTS: The most highly expressed splice variant of VAMP2-NRG1 fusion gene was shown to be membrane bound and display EGF-like domain of NRG1 extracellularly. VAMP2-NRG1 promotes anchorage-independent colony formation of H1568 lung adenocarcinoma cells. Ectopic expression of the fusion gene stimulates phosphorylation of ERBB2 and ERBB3 as well as downstream targets, AKT and ERK, confirming activation of the signaling pathway. CONCLUSION: VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes, which together may form an important diagnostic and clinical category of lung adenocarcinoma cases.
Chen X, etal., Life Sci. 2020 Nov 15;261:118306. doi: 10.1016/j.lfs.2020.118306. Epub 2020 Aug 21.
AIMS: Diabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular disease
s. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM. MATERIALS AND METHODS: DCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine. KEY FINDINGS: Compared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression. SIGNIFICANCE: To our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.
Baik I, etal., Sleep. 2015 Jul 1;38(7):1137-43. doi: 10.5665/sleep.4830.
STUDY OBJECTIVE: There are few studies on gene-environment interactions with obstructive sleep apnea (OSA). Our study aimed to explore genetic polymorphisms associated with OSA using genome-wide association (GWA) data and evaluate the effects of relevant polymorphisms on the association b
etween risk factors, including obesity and alcohol consumption, and OSA. We also investigated on these associations in relation to cerebral white matter hyperintensities (WMH) on magnetic resonance images. DESIGN: A cross-sectional design. SETTING: A polysomnography study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2011-2013. PARTICIPANTS: 1,763 participants aged 48-78 years. RESULTS: 251 individuals were identified to have OSA with an apnea-hypopnea index >= 15. A common polymorphism of neuregulin-1 gene (NRG1), rs10097555, was selected as the most suggestive locus associated with OSA (P value < 10(-5)) based on the results of GWA analysis in a matched case-control subsample (n = 470). Among 1,763 participants, we found that the presence of the NRG1 polymorphism is inversely associated with OSA (P value < 0.01) even after taking into account potential risk factors; the multivariate odds ratio (95% confidence interval) for the mutant alleles was 0.57 (0.39-0.82) compared with the wild-type. We observed that this association is modified by alcohol consumption (P < 0.05), not by obesity. We also observed that WMH are positively associated with OSA independent of the NRG1 polymorphism and alcohol consumption (P < 0.05). CONCLUSIONS: These findings suggest that the neuregulin-1 gene (NRG1) may be involved in the etiological mechanisms of obstructive sleep apnea (OSA) and that carriers of a particular NRG1 mutation may be less likely to have OSA if they do not drink alcoholic beverages.
Nicodemus KK, etal., Arch Gen Psychiatry. 2010 Oct;67(10):991-1001.
CONTEXT: NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis. OBJECTIVE: To examine epistasis between NRG1
;'>NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. DESIGN: Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. PARTICIPANTS: A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). MAIN OUTCOME MEASURES: Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. RESULTS: We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 x ERBB4 interaction modulates downstream AKT1 signaling. CONCLUSION: Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.
Le TL, etal., J Clin Invest. 2021 Mar 15;131(6):e145837. doi: 10.1172/JCI145837.
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with R
ET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
This study aimed to investigate the effect of the neuregulin-1/epidermal growth factor 4 (NRG1/ErbB4) signaling pathway on visual cortex synaptic plasticity in adult amblyopic rats with monocular deprivation (MD). Compared with the control group, the P wave late
ncy and amplitude of the MD group were prolonged and low, respectively, with reduced synaptic plasticity-related protein expression, lower number of visual cortex neurons, and increased apoptosis of visual cortex neurons. Recombinant neuregulin-1 (rNRG1) administration activated the NRG1/ErbB4 signaling pathway and improved the visual cortex synaptic plasticity in MD amblyopic rats. However, the effects of rNRG1 were reversed by AG1478 (ErbB4 receptor blockers). The NRG1/ErbB4 signaling pathway in the parvalbumin neurons from MD rats was also inactivated. Amblyopic rats had significantly low cell activity and downregulated expression of synaptic plasticity-related proteins. Thus, exogenous administration of NRG1 can activate ErbB4 signal transduction and improve the damaged synaptic plasticity of the visual cortex among amblyopic rats. Further studies are warranted to explore the potential for clinical management of amblyopia.
Yoshimi A, etal., Psychiatry Clin Neurosci. 2016 Feb 23. doi: 10.1111/pcn.12384.
AIM: Numerous reports have described differences in the distribution of orbitofrontal cortex (OFC) sulcogyral patterns between patients with schizophrenia (SZ patients) and healthy controls (HCs). Alterations in OFC morphology are also observed in those at high risk for developing SZ and in first-ep
isode SZ, suggesting that genetic associations may be extant in determining OFC sulcogyral patterns. We investigated the association between single nucleotide polymorphisms (SNPs) in NRG1 and OFC sulcogyral patterns. METHODS: A total of 59 Japanese patients diagnosed with SZ and 60 HCs were scanned on a 1.5T magnet. Patients were also assessed clinically. OFC sulcogyral patterns were evaluated for each participant, and genotyping was performed for four SNPs in NRG1 (SNP8NRG243177, SNP8NRG221533, SNP8NRG241930, and rs1081062). RESULTS: There were significant differences in the distribution of OFC sulcogyral patterns between SZ patients and HCs (chi2 = 6.52, p = 0.038). SZ patients showed an increase in the frequency of Type III expression, which was associated with an earlier age of disease onset (beta = -0.302, F = 4.948, p = 0.030). Although no difference was found in genotype frequencies between SZ patients and HCs, an NRG1 SNP, SNP8NRG243177, was associated with Type II expression in SZ patients (beta = 0.237, F = 4.120, p = 0.047). CONCLUSION: Our results suggest that OFC sulcogyral pattern formation in schizophrenia may be associated with NRG1 allele frequency, which is closely related to neurodevelopment.
In this study, we implanted Schwann cells (SCs) transfected with Neuregulin 1 (NRG1) gene into rats with hemisection spinal cord injury, determined its effects on the repair of spinal cord injury and investigated the underlying mechanisms. Primary SCs were cultu
red, purified, and transfected with NRG1 gene. SCs and SCs transfected with NRG1 gene were implanted, respectively, into rats with hemisection spinal cord injury. Behavior, imaging, electrophysiology, and immuno-histological analyses were performed to evaluate the effect of NRG1 gene-transfected SCs on the repair of spinal cord injury. In vitro studies showed that NRG1 protein was highly expressed in SCs transfected with NRG1 gene. In addition, the receptors for NRG1, ErbB2, and ErbB4, were upregulated in a time-dependent manner. NRG1-transfected SCs secreted large amount of NRG1 proteins in vivo, which efficiently promoted the expression of ErbB2 and ErbB4 in the neurons and neuroglia cells. Moreover, the number of NSE- and GFAP-positive cells was increased. After cell transplantation, many transplanted cells survived and migrated to the areas with spinal cord injuries. The injuries were recovered in all the experimental groups, but the most significant recovery was observed in the group of rats implanted with SCs transfected with NRG1 gene. We conclude that NRG1-transfected SCs can significantly increase the effect on the repair of spinal cord injury. This repair effect is achieved via the upregulation of ErbB receptor in the target cells, increased proliferation of glial cells, and protection of neurons from apoptosis.
Tang D, etal., Am J Cancer Res. 2020 Aug 1;10(8):2582-2595. eCollection 2020.
The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes, and its genetic variation and functional dysregulation are involved in pathogenesis of several cancers. To systematically evaluate the role of NLRP3 in predicting outcomes of patients with non-small cell lung can
cer (NSCLC), we performed a two-phase analysis for associations between genetic variants in NLRP3 inflammasome pathway genes and NSCLC survival by using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We used multivariate Cox proportional hazards regression analysis with Bayesian false discovery probability (<=0.80) for multiple testing correction to evaluate associations between 20,730 single-nucleotide polymorphisms (SNPs) in 176 genes and overall survival of 1,185 NSCLC patients from the PLCO trial. We further validated the identified significant SNPs in another GWAS dataset with survival data from 984 NSCLC patients of the Harvard Lung Cancer Susceptibility (HLCS) study. The results showed that two independent SNPs in two different genes (i.e., BIRC3 rs11225211 and NRG1 rs4733124) were significantly associated with the NSCLC overall survival, with a combined hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.74-0.93 and P = 0.0009] and 1.18 (95% CI = 1.06-1.31) and P = 0.002], respectively. However, further expression quantitative trait loci (eQTL) analysis showed no evidence for correlations between the two SNPs and mRNA expression levels of corresponding genes. These results indicated that genetic variants in the NLRP3 imflammasome pathway gene-sets might be predictors of NSCLC survival, but the molecular mechanisms underlying the observed associations warrant further investigations.
The adult spinal cord contains a pool of endogenous glial precursor cells, which spontaneously respond to spinal cord injury (SCI) with increased proliferation. These include oligodendrocyte precursor cells that express the NG2 proteoglycan and can differentiate into mature oligodendrocytes. Thus, a
potential approach for SCI treatment is to enhance the proliferation and differentiation of these cells to yield more functional mature glia and improve remyelination of surviving axons. We previously reported that soluble glial growth factor 2 (GGF2)- and basic fibroblast growth factor 2 (FGF2)-stimulated growth of NG2(+) cells purified from injured spinal cord in primary culture. This study examines the effects of systemic administration of GGF2 and/or FGF2 after standardized contusive SCI in vivo in both rat and mouse models. In Sprague-Dawley rats, 1 week of GGF2 administration, beginning 24 h after injury, enhanced NG2(+) cell proliferation, oligodendrogenesis, chronic white matter at the injury epicenter, and recovery of hind limb function. In 2',3'-cyclic-nucleotide 3'-phosphodiesterase-enhanced green fluorescent protein mice, GGF2 treatment resulted in increased oligodendrogenesis and improved functional recovery, as well as elevated expression of the stem cell transcription factor Sox2 by oligodendrocyte lineage cells. Although oligodendrocyte number was increased chronically after SCI in GGF2-treated mice, no evidence of increased white matter was detected. However, GGF2 treatment significantly increased levels of P0 protein-containing peripheral myelin, produced by Schwann cells that infiltrate the injured spinal cord. Our results suggest that GGF2 may have therapeutic potential for SCI by enhancing endogenous recovery processes in a clinically relevant time frame.
Kim SH, etal., PLoS Pathog. 2015 Nov 20;11(11):e1005308. doi: 10.1371/journal.ppat.1005308. eCollection 2015 Nov.
The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic c
olonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation.
Seshadri S, etal., Nat Commun. 2015 Dec 11;6:10118. doi: 10.1038/ncomms10118.
Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. H
ere we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits.
Han S, etal., Biol Psychiatry. 2012 Oct 15;72(8):637-44. doi: 10.1016/j.biopsych.2012.02.038. Epub 2012 Apr 19.
BACKGROUND: A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. METHODS: We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for C
aD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. RESULTS: We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). CONCLUSIONS: Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples.
Epidemiological studies suggest that early life infections may contribute to the development of psychiatric disorders characterized by cognitive deficits. Here, we studied the effects of a neonatal influenza A/WSN/33 virus infection on locomotor activity, working memory and emotional behavior in adu
lt mice. In addition to wild type mice, immunodeficient (Tap1(-/-)) mice lacking functional CD8(+) T cells, were included in the study to model the potential influence of a genetic deficit relating to virus clearance. Three to four months after the infection, infected Tap1(-/-) mice, but not wild type mice, exhibited deficits in working memory as well as increased rearing activity and anxiety. In the medial prefrontal cortices of these infected Tap1(-/-) mice reduced levels of type III Nrg1 transcripts were observed supporting a role for neuregulin 1 signaling in neuronal circuits involved in working memory. Virus replication, distribution or clearance did not differ between the two genotypes. The lack of CD8(+) T cells, however, appeared to contribute to a more pronounced glia response in Tap1(-/-) than in wild type mice. Thus, the present study suggest that the risk of developing deficits in cognitive and emotional behavior following a CNS infection during brain development is influenced by genetic variation in genes involved in the immune response.
In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells in
duce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.
Han ME, etal., J Gastroenterol. 2015 Jun;50(6):645-56. doi: 10.1007/s00535-014-1008-1. Epub 2014 Nov 8.
BACKGROUND: Gastric cancer stem cells (GCSCs) have been successfully isolated from patients. However, the molecular mechanisms underlying the self-renewal of GCSCs and their relationship with the microenvironment are poorly characterized. METHODS: GCSCs and cancer-associated fibroblasts (CAFs) were
cultured directly from gastric cancer patients. The self-renewal of GCSCs was assayed by sphere formation assay and in vivo tumorigenicity. Expression of neuregulin1 (NRG1) was examined by immunohistochemistry, real-time PCR and western blotting. RESULTS: CAFs increased the self-renewal of GCSCs by secreting NRG1. NRG1 activated NF-kappaB signaling and this activation regulated GCSC self-renewal. Moreover, NF-kappaB-active GCSCs were tumorigenic, however NF-kappaB-inactive GCSCs were not. The overexpression of NRG1 in stromal cells and cancer cells was observed in the tumor tissues of gastric cancer patients and was associated with clinical stage lymph node metastasis and survival in gastric cancer patients. In addition, we also found that NRG1 can regulate the proliferation and invasion of gastric cancer cells. CONCLUSIONS: These results indicate that NRG1, which can be secreted by CAFs or cancer cells, promotes progression of gastric cancer by regulating the self-renewal of GCSCs and its overexpression is associated with a prognosis of gastric cancer.
OBJECTIVES: LIM homeobox transcription factor 1, alpha (LMX1A) and neuregulin 1 (NRG1) are susceptibility genes for schizophrenia that have been implicated in the dopaminergic pathway and have been associated with altered cognitive functioning. We hypothesized t
hat single nucleotide polymorphisms (SNPs) in LMX1A and NRG1 would be associated with cognitive functioning in bipolar disorder. METHODS: In total, four SNPs were directly genotyped. Regression models with five aggregated cognitive domains and intelligence quotient (IQ) score were run using risk variants of LMX1A (rs11809911, rs4657412, rs6668493) and NRG1 (rs35753505) as predictors. Models were performed in a clinical sample of patients with bipolar disorder (n = 114) and healthy controls (n = 104). RESULTS: The risk variants of the rs11809911 SNP in LMX1A were negatively associated with IQ score and memory/learning, whereas the risk variants of rs35753505 in NRG1 were positively associated with IQ score (adjusted R(2) = 0.17, Q = 0.006) and memory/learning (adjusted R(2) = 0.24, Q = 0.001). The risk variants of the rs35753505 SNP in NRG1 were positively associated with language (adjusted R(2) = 0.11, Q = 0.006), visuospatial functions (adjusted R(2) = 0.23, Q = 0.001), and attention/speed (adjusted R(2) = 0.25, Q = 0.001). Results could not be replicated in controls. CONCLUSIONS: The risk variants of the rs35753505 SNP were associated with increased performance in several cognitive domains and IQ, whereas the risk variants of the rs11809911 SNP in LMX1A was associated with reduced IQ and memory/learning.
Dexamethasone is a commonly used synthetic glucocorticoid in the clinic. As a compound that can cross the placental barrier to promote fetal lung maturation, dexamethasone is extensively used in pregnant women at risk of premature delivery. However, the use of glucocorticoids during pregnancy increa
ses the risk of neurodevelopmental disorders. In the present study, we observed anxiety- and depressive-like behavior changes and hyperexcitability of hippocampal neurons in adult rat offspring with previous prenatal dexamethasone exposure (PDE); the observed changes were related to in utero damage of parvalbumin interneurons. A programmed change in neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ErbB4) signaling was the key to the damage of parvalbumin interneurons in the hippocampus of PDE offspring. Anxiety- and depressive-like behavior, NRG1-ErbB4 signaling activation, and damage of parvalbumin interneurons in PDE offspring were aggravated after chronic stress. The intervention of NRG1-ErbB4 signaling contributed to the improvement in dexamethasone-mediated injury to parvalbumin interneurons. These results suggested that PDE might cause anxiety- and depressive-like behavior changes in male rat offspring through the programmed activation of NRG1-ErbB4 signaling, resulting in damage to parvalbumin interneurons and hyperactivity of the hippocampus. Intrauterine programming of neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ERBB4) overactivation by dexamethasone mediates anxiety- and depressive-like behavior in male rat offspring.
