ARIA: A Neuromuscular Junction Neuregulin

Fischbach, Gerald D.; Rosen, Kenneth M.

doi:10.1146/annurev.neuro.20.1.429

Cited by 256 publications

(189 citation statements)

References 146 publications

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“…NRG-1 binds to its receptor, ErbB, and NRG-1-ErbB signaling plays multiple roles in development and plasticity in the central nervous system. 13 Type I is prominently expressed early in development; type II is abundantly expressed in the adult nervous system; and type III is the major isoform produced by sensory neurons and motorneurons, and is also expressed in the rodent brain. 27 Little is known about NRG-1 expression in human brain; however, NRG-1 is present in neuronal cell bodies and synapse-rich regions in the hippocampus and type II isoform is expressed in oligodendrocytes, astrocytes, and microglia.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 NRG-1 is one of the neuregulin family of proteins, which have a broad range of bioactivities in the central nervous system and contain an epidermal growth factor (EGF)-like motif that activates membrane-associated tyrosine kinases related to ErbB receptors. 13 The EGF-like domain of NRG-1 is required for ErbB receptor binding, dimerization, tyrosine phosphorylation, and activation of downstream signaling pathways. 14 A gene-targeting approach for NRG-1-ErbB signaling revealed a behavioral phenotype in mice that overlaps with certain animal models for schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

et al. 2003

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Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and b-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

et al. 2003

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“…Neuregulin-1 is a protein able to induce transcription of nAChR subunits in myotubes. 45 It might be interesting to associate neuregulin-1 with the soluble agrin in the experiment of agrin-induced nAchRs clustering and look for an eventual effect on nAChRs expression in the SMA I myotubes. It will also be necessary to study other proteins involved in the NMJ installation such as rapsyn.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

Arnold¹,

Gueye²,

Guettier‐Sigrist³

et al. 2004

Laboratory Investigation

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motoneurons and skeletal muscle atrophy. In its most severe form, it leads to death before the age of 2 years. While primary degeneration of motor neurons is well established in this disease, and this results in neurogenic atrophy of skeletal muscle, we have previously reported evidence for a primary muscle defect. In this study, we used primary cultures of embryonic human skeletal muscle cells from patients with SMA and from controls to examine the effects of muscle fiber differentiation in the absence of a nerve component. Cultured SMA skeletal muscle cells are unable to fuse correctly to form multinuclear myotubes, the precursors of the myofibers. We also show that agrin-induced aggregates of nicotinic acetylcholine receptors, one of the earliest steps of neuromuscular junction formation, cannot be visualized by confocal microscopy on cells from SMA patients. In binding experiments, we demonstrate that this lack of clustering is due to defective expression of the nicotinic acetylcholine receptors in the myotubes of SMA patients whereas the affinity of a-bungarotoxin for its receptor remains unchanged regardless of muscle cell type (SMA or control). These observations suggest that muscle cells from SMA patients have intrinsic abnormalities that may affect proper formation of the neuromuscular junction. Keywords: spinal muscular atrophy; myotubes; neuromuscular junction; nicotinic acetylcholine receptors; aggregation; binding Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of spinal motor neurons leading to a muscle weakness and paralysis. SMA is traditionally classified into three types based on the age of onset and the severity of symptoms. 1 The SMA I or Werdnig-Hoffmann disease is the most severe form. Patients never attain the ability to sit, and their lifespan does not exceed infancy in most cases. SMA II is the intermediate form. Patients are unable to stand or walk unaided, and death usually occurs in adulthood. SMA III or Kugelberg-Welander disease presents a milder phenotype. Patients are able to stand and walk and present a near-normal life expectancy. The gene responsible for all three types of SMA was mapped to the region 5q11.2-13.3 by linkage analysis. [2][3][4][5] This gene, named SMN for 'survival of motor neurons', is mutated in 98% of the SMA patients, and the majority of mutations occur in exon 7. 6 It encodes a ubiquitously expressed SMN protein present in both the cytoplasm and the nucleus. In this last compartment, the SMN protein is concentrated in structures called gems (for 'gemini of coiled bodies') located in the close proximity of Cajal bodies (previously named coiled bodies). 7,8 The SMN protein participates in the formation of the SMN complex, which is associated with small nuclear ribonucleoproteins (snRNP) in the cytoplasm and plays a crucial role in the spliceosomal snRNP assembly. 9 In the nucleus, the SMN complex participates in the regener...

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“…Four genes encoding NRGs have been identified [NRG1-4 (18,19)]. Of these, NRG1 is the best-characterized and is known for its biological activities described as glial growth factor (GGF) and the acetylcholine receptorinducing activity [ARIA (20)(21)(22)(23)(24)]. Although Ͼ15 alternatively spliced variants of NRG1 have been identified, these can be grouped into three main classes (I, II, and III) based upon the structure of their extracellular regions (18).…”

mentioning

confidence: 99%

The role of neuregulin–ErbB4 interactions on the proliferation and organization of cells in the subventricular zone

Ghashghaei

Weber

Pevny

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

154

129

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Coordinated regulation of neuronal progenitor differentiation in the subventricular zone (SVZ) is a fundamental feature of adult neurogenesis. However, the molecular control of this process remains mostly undeciphered. Here, we investigate the role of neuregulins (NRGs) in this process and show that a NRG receptor, ErbB4, is primarily expressed by polysialylated neural cell adhesion molecule immature neuroblasts but is also detected in a subset of GFAP ؉ astroglial cells, ependymal cells, and Dlx2 ؉ precursors in the SVZ. Of the NRG ligands, both NRG1 and -2 are expressed by immature polysialylated neural cell adhesion molecule neuroblasts in the SVZ. NRG2 is also expressed by some of the GFAP ؉ putative stem cells lining the ventricles. Infusion of exogenous NRG1 leads to rapid aggregation of Dlx2 ؉ cells in the SVZ and affects the initiation and maintenance of organized neuroblast migration from the SVZ toward the olfactory bulb. In contrast, the infusion of NRG2 increased the number of Sox2 and GFAP ؉ precursors in the SVZ. An outcome of this NRG2 effect is an increase in the number of newly generated migrating neuroblasts in the rostral migratory stream and GABAergic interneurons in the olfactory bulb. The analysis of conditional null mice that lack NRG receptor, ErbB4, in the nervous system revealed that the observed activities of NRG2 require ErbB4 activation. These results indicate that different NRG ligands affect distinct populations of differentiating neural precursors in the neurogenic regions of the mature forebrain. Furthermore, these studies identify NRG2 as a factor capable of promoting SVZ proliferation, leading to the formation of new neurons in vivo.adult neurogenesis ͉ rostral migratory stream ͉ schizophrenia T he primary sites of neurogenesis in the adult rodent brain are in the hippocampus and the forebrain subventricular zone [SVZ (1-9)]. The multipotential cells in the SVZ are believed to give rise to a collection of migrating neural progenitors that form the rostral migratory stream (RMS). These cells transit from the anterior SVZ to the olfactory bulb and appear to migrate tangentially along each other through tubes composed of astrocytic-like glial cells (3, 4). Upon their arrival at the posterior core of the olfactory bulb, the cells exit the RMS, switch from a tangential to radial mode of migration, and differentiate into functional granule interneurons or periglomerular interneurons (10, 11).The observation that the receptor tyrosine kinase ErbB4 is selectively expressed at high levels in the SVZ and RMS (12) suggests a possible role for the ErbB4 ligands, the neuregulins (NRGs), as modulators of the proliferation and migration of neural stem and progenitor cells. The NRGs are a collection of related polypeptides characterized by the presence of a single EGF-like domain, capable of binding to and activating ErbB receptors, of which there are four members, ErbB1-4. NRGs serve as ligands for ErbB4 (13) and ErbB3 (14-16) but can be potent activators of ErbB2 and weak activators of the E...

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ARIA: A Neuromuscular Junction Neuregulin

Cited by 256 publications

References 146 publications

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

The role of neuregulin–ErbB4 interactions on the proliferation and organization of cells in the subventricular zone

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