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Gerald D. Fischbach - One of the best experts on this subject based on the ideXlab platform.
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Differentiation-dependent regulation of skeletal myogenesis by Neuregulin-1.
Biochemical and biophysical research communications, 2003Co-Authors: Byron D. Ford, Bomie Han, Gerald D. FischbachAbstract:Neuregulins comprise a group of growth factor proteins that regulate the differentiation of skeletal muscle. Here, we report that Neuregulins are regulators of myogenic differentiation and stimulate mitogenesis in L6 skeletal myoblasts. The mitogenic response to Neuregulin-1 was differentiation-dependent and observed only in aligned, differentiating cells. Treatment of these cells with Neuregulin-1 increased [ 3 H]thymidine incorporation and cell proliferation by 2- to 5-fold, while a minimal increase was seen in proliferating myoblasts. Neuregulin-1 did not induce DNA synthesis in fused, multinucleated myotubes. The increased DNA synthesis correlated with downregulation of myogenin and inhibition of myoblast fusion and myotube formation. These data suggest that Neuregulins may regulate skeletal myogenesis in vivo and that this regulation is dependent on the state of differentiation of the myocytes.
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Neuregulin: an oligodendrocyte growth factor absent in active multiple sclerosis lesions.
Developmental neuroscience, 2001Co-Authors: Andrea Viehover, Gerald D. Fischbach, Robert H. Miller, Song Kyu Park, Timothy VartanianAbstract:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which results in demyelination and axonal injury. Conventional therapy for MS is immune suppression in the absence of agents that promote neural and glial survival or remyelination. Neuregulins are a family of ligands that exert trophic effects on both neurons and glia. Using mice bearing a null mutation in the Neuregulin gene, here we demonstrate that Neuregulins are necessary for the normal development of oligodendrocytes. In addition, Neuregulins are produced in the normal human CNS by astrocytes as well as neurons. Astrocyte-derived Neuregulin is functionally active in bioassays and exists in secreted and membrane-associated beta-isoforms. In active and chronic active MS lesions, however, the expression of astrocyte Neuregulin is dramatically reduced. The absence of Neuregulin in active MS lesions may contribute to the paucity of remyelination in MS.
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Neuregulin and erbb receptor signaling pathways in the nervous system
Current Opinion in Neurobiology, 2001Co-Authors: Andres Buonanno, Gerald D. FischbachAbstract:Abstract The Neuregulins are a complex family of factors that perform many functions during neural development. Recent experiments have shown that Neuregulins promote neuronal migration and differentiation, and regulate the selective expression of neurotransmitter receptors in neurons and at the neuromuscular junction. They also regulate glial commitment, proliferation, survival and differentiation. At interneuronal synapses, Neuregulin ErbB receptors associate with PDZ-domain proteins at postsynaptic densities where they can modulate synaptic plasticity. How this combinatorial network — comprising many Neuregulin ligands that signal through distinct combinations of dimeric ErbB receptors — elicits its multitude of biological effects is beginning to be resolved.
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Neuregulin stimulates DNA synthesis in embryonic chick heart cells.
Developmental biology, 1999Co-Authors: Byron D. Ford, Jeffrey A. Loeb, Gerald D. FischbachAbstract:Neuregulins are a family of growth factors that have been shown to promote the growth or differentiation of various cell types. Recently, targeted mutations of the genes for Neuregulins or their putative receptors by homologous recombination resulted in embryonic lethality characterized by cardiac malformation. Here we investigate a role for Neuregulin in the growth of cultured chick heart cells. Neuregulin induced the tyrosine phosphorylation of a 185-kDa protein in cultured heart cells, and it also stimulated an increase in [(3)H]thymidine incorporation and BrDU labeling in the cell cultures. Immunocytochemistry revealed that the increased DNA synthesis was primarily in mesenchymal cells and not detected in myocytes or endocardial cells. These data suggest that Neuregulin may function as a paracrine signal in mesenchymal-endothelial interactions during cardiac development.
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Failure of spinal cord oligodendrocyte development in mice lacking Neuregulin.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Timothy Vartanian, Gerald D. Fischbach, Robert H. MillerAbstract:Oligodendrocytes develop from a subpopulation of precursor cells within the ventral ventricular zone of the spinal cord. The molecular cues that direct this spatially and temporally restricted event seem to originate in part from structures ventral to and within the spinal cord. Here, we present evidence that the family of ligands termed Neuregulins are necessary for the normal generation of mouse spinal cord oligodendrocytes. Oligodendrocytes mature in spinal cord explants from wild-type mice and mice heterozygotic for a null mutation in the Neuregulin gene (NRG +/−) in a temporal sequence of developmental events that replicates that observed in vivo. However, in spinal cord explants derived from mice lacking Neuregulin (NRG −/−), oligodendrocytes fail to develop. Addition of recombinant Neuregulin to spinal cord explants from NRG −/− mice rescues oligodendrocyte development. In wild-type spinal cord explants, inhibitors of Neuregulin mimic the inhibition of oligodendrocyte development that occurs in NRG −/− explants. In embryonic mouse spinal cord, Neuregulins are present in motor neurons and the ventral ventricular zone where they likely exert their influence on early oligodendrocyte precursor cells.
Mark A. Marchionni - One of the best experts on this subject based on the ideXlab platform.
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Neuregulins regulate cardiac parasympathetic activity muscarinic modulation of beta adrenergic activity in myocytes from mice with Neuregulin 1 gene deletion
Circulation, 2004Co-Authors: Katashi Okoshi, Mark A. Marchionni, Masaharu Nakayama, Xinhua Yan, Marina Politi Okoshi, Adam J T Schuldt, Beverly H LorellAbstract:Background— Neuregulins are required for maintenance of acetylcholine receptor–inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of Neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances β-adrenergic activation. To test the hypothesis that Neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for Neuregulin-1 gene deletion (NRG-1+/−) and examined the effects of β-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol. Methods and Results— We evaluated contraction and intracellular Ca2+ transients ([Ca2+]i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1+/− and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25°C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca2+]i were not different between WT and NRG-1+/− mice. The steady-state increas...
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Neuregulins Promote Survival and Growth of Cardiac Myocytes PERSISTENCE OF ErbB2 AND ErbB4 EXPRESSION IN NEONATAL AND ADULT VENTRICULAR MYOCYTES
Journal of Biological Chemistry, 1998Co-Authors: You Yang Zhao, Mark A. Marchionni, Douglas R. Sawyer, Ragavendra R. Baliga, Douglas J Opel, Ralph A KellyAbstract:Abstract Neuregulins (i.e. Neuregulin-1 (NRG1), also called neu differentiation factor, heregulin, glial growth factor, and acetylcholine receptor-inducing activity) are known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. Unexpectedly, mice with loss of function mutations of NRG1 or of either of two of their cognate receptors, ErbB2 and ErbB4, die during midembryogenesis due to the aborted development of myocardial trabeculae in ventricular muscle. To examine the role of NRG and their receptors in developing and postnatal myocardium, we studied the ability of a soluble NRG1 (recombinant human glial growth factor 2) to promote proliferation, survival, and growth of isolated neonatal and adult rat cardiac myocytes. Both ErbB2 and ErbB4 receptors were found to be expressed by neonatal and adult ventricular myocytes and activated by rhGGF2. rhGGF2 (30 ng/ml) provoked an approximate 2-fold increase in embryonic cardiac myocyte proliferation. rhGGF2 also promoted survival and inhibited apoptosis of subconfluent, serum-deprived myocyte primary cultures and also induced hypertrophic growth in both neonatal and adult ventricular myocytes, which was accompanied by enhanced expression of prepro-atrial natriuretic factor and skeletal α-actin. Moreover, NRG1 mRNA could be detected in coronary microvascular endothelial cell primary cultures prepared from adult rat ventricular muscle. NRG1 expression in these cells was increased by endothelin-1, another locally acting cardiotropic peptide within the heart. The persistent expression of both a Neuregulin and its cognate receptors in the postnatal and adult heart suggests a continuing role for Neuregulins in the myocardial adaption to physiologic stress or injury.
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Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete Neuregulin, and show constitutive activation of erbB3 receptors: evidence for a Neuregulin autocrine loop.
Experimental neurology, 1997Co-Authors: Claudia Rosenbaum, Mark A. Marchionni, Saikumar Karyala, Haesun A. Kim, Alexei L. Krasnoselsky, Beth Happel, Indu Isaacs, Robert Brackenbury, Nancy RatnerAbstract:Abstract Cultured Schwann cells secreted low levels (30 pg/ml/1.5 × 10 6 cells) of a 45-kDa Neuregulin protein and showed constitutive activation of a Neuregulin receptor, Erb-B3, suggesting the existence of an autocrine loop involving Neuregulins in Schwann cells. RT-PCR analyses indicated that Schwann cells and fibroblasts in culture produced SMDF/n-ARIA and NDF but not GGF Neuregulin messages. Schwann cell and fibroblast Neuregulin messages encoded both β and α domains; Schwann cell transcripts encoded only transmembrane Neuregulin forms while fibroblast messages encoded transmembrane and secreted forms. SMDF/n-ARIA and NDF messages were also expressed in early postnatal rat sciatic nerve, suggesting a role for Neuregulins in peripheral nerve development. An anti-Neuregulin antibody inhibited the mitogenic response of Schwann cells to cultured neurons and to extracts of cultured neurons or embryonic brain, consistent with the accepted paracrine role of Neuregulins on Schwann cells. Surprisingly, the same antibody inhibited Schwann cell proliferation stimulated by several unrelated mitogens including bFGF, HGF, and TGF-β1. These data implicate both paracrine and autocrine pathways involving Neuregulin form(s) in Schwann cell mitogenic responses.
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ggf Neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors
Neuron, 1996Co-Authors: Peter Canoll, Mark A. Marchionni, Josem Musacchio, Rebecca Hardy, Richard Reynolds, James L. SalzerAbstract:We show that GGF/Neuregulin is a mitogen for prooligodendrocytes (O4+/O1- cells), oligodendrocytes (O4+/O1+ cells), and type-2 astrocytes. Heregulin beta 1, another Neuregulin isoform, is also mitogenic. The proliferative effect of glial growth factor (GGF) does not require, but is greatly potentiated by, serum factors. GGF also promotes the survival of pro-oligodendrocytes under serum-free conditions. High levels of GGF reversibly inhibit the differentiation and lineage commitment of oligodendrocyte progenitors and, in differentiated cultures, result in loss of O1 and myelin basic protein expression. All three erbB receptors are expressed by progenitors and are activated by GGF; the relative abundance of these receptors changes during differentiation. Finally, cortical neurons release a soluble mitogen for pro-oligodendrocytes that is specifically blocked by antibodies to GGF. These results implicate the Neuregulins in the neuronal regulation of oligodendrocyte progenitor proliferation, survival, and differentiation.
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Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression.
Nature, 1995Co-Authors: Sangmee Ahn Jo, Mark A. Marchionni, Steven J BurdenAbstract:TWO different signalling pathways mediate the localization of acetylcholine receptors (AChRs) to synaptic sites in skeletal muscle. The signal for one pathway is agrin, a protein that triggers a redistribution of previously unlocalized cell surface AChRs to synaptic sites1. The signal for the other pathway is not known, but this signal stimulates transcription of AChR genes in myofibre nuclei near the synaptic site2. Neuregulins, identified originally as a potential ligand for erbB2 (Neu differentiation factor, NDF) 3, stimulate proliferation of Schwann cells (glial growth factor, GGF) 4, increase the rate of AChR synthesis in cultured muscle cells (AChR-inducing activity) 5 and are expressed in motor neurons4,5. These results raise the possibility that Neuregulin is the signal that activates AChR genes in synaptic nuclei. Here we show that Neuregulin activates AChR gene expression in C2 muscle cells and that the Neuregulin response element in the AChR δ-subunit gene is contained in the same 181 base pairs that confer synapse-specific expression in transgenic mice. We use antibodies to show that Neuregulins are concentrated at synaptic sites and that, like the extracellular signal that stimulates synapse-specific expression, Neuregulins remain at synaptic sites in the absence of nerve and muscle. We show that C2 muscle cells contain erbB2 and erbB3 messenger RNA but little or no erbB4 mRNA, and that Neuregulin stimulates tyrosine phosphorylation of erbB2 and erbB3, indicating that Neuregulin signalling in skeletal muscle may be mediated by a complex of erbB2 and erbB3.
Byron D. Ford - One of the best experts on this subject based on the ideXlab platform.
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Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke
Biochemical and biophysical research communications, 2004Co-Authors: Ju Jiang, Gregory D. Ford, Byron D. FordAbstract:Recent work from our laboratory demonstrated that the expression Neuregulin-1 in neurons was induced in the ischemic penumbra by focal stroke in the rat. Here, we show that a single intravascular injection of Neuregulin-1beta (approximately 2.5 ng/kg) reduced cortical infarct volume by >98% when given immediately before middle cereral artery occlusion. Subcortical infarct volume was reduced by approximately 40%. Analysis of DNA fragmentation in brain tissues indicated that Neuregulin-1 blocked apoptosis in cortical neurons in the penumbra. Neuregulin-1 prevented macrophage/microglial infiltration and astrocytic activation following focal ischemia. The neuroprotective effect of Neuregulin-1 was also associated with a suppression of interleukin-1beta mRNA levels. These data suggest that Neuregulin-1 protects neurons from delayed, ischemia-induced apoptotic cell death in the cortex by inhibiting pro-inflammatory responses. Neuregulins represent a novel, potent neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.
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Differentiation-dependent regulation of skeletal myogenesis by Neuregulin-1.
Biochemical and biophysical research communications, 2003Co-Authors: Byron D. Ford, Bomie Han, Gerald D. FischbachAbstract:Neuregulins comprise a group of growth factor proteins that regulate the differentiation of skeletal muscle. Here, we report that Neuregulins are regulators of myogenic differentiation and stimulate mitogenesis in L6 skeletal myoblasts. The mitogenic response to Neuregulin-1 was differentiation-dependent and observed only in aligned, differentiating cells. Treatment of these cells with Neuregulin-1 increased [ 3 H]thymidine incorporation and cell proliferation by 2- to 5-fold, while a minimal increase was seen in proliferating myoblasts. Neuregulin-1 did not induce DNA synthesis in fused, multinucleated myotubes. The increased DNA synthesis correlated with downregulation of myogenin and inhibition of myoblast fusion and myotube formation. These data suggest that Neuregulins may regulate skeletal myogenesis in vivo and that this regulation is dependent on the state of differentiation of the myocytes.
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Neuregulin expression after focal stroke in the rat
Neuroscience letters, 2002Co-Authors: Marcus W. Parker, Yong Chen, John M. Hallenbeck, Byron D. FordAbstract:Upregulation of Neuregulin has been demonstrated in traumatic brain injury, but a role for Neuregulin in ischemic brain injury has not been investigated. Therefore, we used a rat permanent middle cerebral artery occlusion model to examine the distribution of Neuregulin after the onset of ischemic stroke. We found an increase in immunohistochemical staining for Neuregulin in the penumbral regions of the cortex. The increase in Neuregulin appeared to be neuronal. There was no Neuregulin co-localization with astrocytes or macrophages. These results demonstrate that Neuregulin is induced in neurons following ischemic stroke and may be involved in neuroprotection and repair.
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Neuregulin stimulates DNA synthesis in embryonic chick heart cells.
Developmental biology, 1999Co-Authors: Byron D. Ford, Jeffrey A. Loeb, Gerald D. FischbachAbstract:Neuregulins are a family of growth factors that have been shown to promote the growth or differentiation of various cell types. Recently, targeted mutations of the genes for Neuregulins or their putative receptors by homologous recombination resulted in embryonic lethality characterized by cardiac malformation. Here we investigate a role for Neuregulin in the growth of cultured chick heart cells. Neuregulin induced the tyrosine phosphorylation of a 185-kDa protein in cultured heart cells, and it also stimulated an increase in [(3)H]thymidine incorporation and BrDU labeling in the cell cultures. Immunocytochemistry revealed that the increased DNA synthesis was primarily in mesenchymal cells and not detected in myocytes or endocardial cells. These data suggest that Neuregulin may function as a paracrine signal in mesenchymal-endothelial interactions during cardiac development.
Jeffrey A. Loeb - One of the best experts on this subject based on the ideXlab platform.
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Differential distribution of Neuregulin in human brain and spinal fluid.
Brain research, 2008Co-Authors: Mark S. Pankonin, Jasloveleen Sohi, John Kamholz, Jeffrey A. LoebAbstract:The Neuregulins are a family of polypeptide factors implicated in a wide range of neurological and psychiatric disorders including multiple sclerosis, schizophrenia, and Alzheimer's disease. Many alternatively-spliced forms of the NRG1 gene are released as soluble factors that can diffuse to near and distant sites within the nervous system where they can accumulate through binding to highly specific heparan-sulfate proteoglycans in the extracellular matrix. Here we have determined the sites of synthesis and accumulation of heparin-binding Neuregulin forms in human neocortex, white matter, cerebral spinal fluid, and serum by immunostaining and measurement of Neuregulin activity. While Neuregulin precursors are expressed predominately within cortical neurons, soluble Neuregulin accumulates preferentially on the surface of white matter astrocytes. Consistently, Neuregulin activity can be released from the extracellular matrix of human brain by protease treatment. Neuregulin activity is also detectable in human cerebral spinal fluid where its expression appears to be altered in neuronal disorders. While cerebral spinal fluid Neuregulin levels were unaltered in patients with multiple sclerosis, they were slightly reduced in amyotrophic lateral sclerosis and Parkinson's disease (p
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Neuregulins: versatile growth and differentiation factors in nervous system development and human disease.
Brain research reviews, 2006Co-Authors: Raymond M. Esper, Mark S. Pankonin, Jeffrey A. LoebAbstract:The Neuregulins are a family of growth and differentiation factors with a wide range of functions in the nervous system. The power and diversity of the Neuregulin signaling system comes in part from a large number of alternatively-spliced forms of the NRG1 gene that can produce both soluble and membrane-bound forms. The soluble forms of Neuregulin are unique from other factors in that they have a structurally distinct heparin-binding domain that targets and potentiates its actions. In addition, a finely tuned, bidirectional mechanism regulates when and where Neuregulin is released from neurons in response to neurotrophic factors produced by both neuronal targets and supporting glial cells. Together, this produces a balanced intercellular signaling system that can be localized to distinct regions for both normal development and maintenance of the mature nervous system. Recent evidence suggests that Neuregulin signaling plays important roles in many neurological disorders including multiple sclerosis, traumatic brain and spinal cord injury, peripheral neuropathy, and schizophrenia. Here, we review the basic biology of Neuregulins and relate this to research suggesting their involvement with and potential therapeutic uses for neurological disorders.
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Specific structural features of heparan sulfate proteoglycans potentiate Neuregulin-1 signaling.
The Journal of biological chemistry, 2004Co-Authors: Mark S. Pankonin, John T. Gallagher, Jeffrey A. LoebAbstract:Neuregulins are a family of growth and differentiation factors that act through activation of cell-surface erbB receptor tyrosine kinases and have essential functions both during development and on the growth of cancer cells. One alternatively spliced Neuregulin-1 form has a distinct heparin-binding immunoglobulin-like domain that enables it to adhere to heparan sulfate proteoglycans at key locations during development and substantially potentiates its activity. We examined the structural specificity needed for Neuregulin-1-heparin interactions using a gel mobility shift assay together with an assay that measures the ability of specific oligosaccharides to block erbB receptor phosphorylation in L6 muscle cells. Whereas the N-sulfate group of heparin was most important, the 2-O-sulfate and 6-O-sulfate groups also contributed to Neuregulin-1 binding in these two assays. Optimal binding to Neuregulin-1 required eight or more heparin disaccharides; however, as few as two disaccharides were still able to bind Neuregulin-1 to a lesser extent. The physiological importance of this specificity was shown both by chemical and siRNA treatment of cultured muscle cells. Pretreatment of muscle cells with chlorate that blocks all sulfation or with an siRNA that selectively blocks N-sulfation significantly reduced erbB receptor activation by Neuregulin-1 but had no effect on the activity of Neuregulin-1 that lacks the heparin-binding domain. These results suggest that the regulation of glycosaminoglycan sulfation is an important biological mechanism that can modulate both the localization and potentiation of Neuregulin-1 signaling.
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Rapid Axoglial Signaling Mediated by Neuregulin and Neurotrophic Factors
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004Co-Authors: Raymond M. Esper, Jeffrey A. LoebAbstract:During peripheral nervous system development, Schwann cells are precisely matched to the axons that they support. This is mediated by axonal Neuregulins that are essential for Schwann cell survival and differentiation. Here, we show that sensory and motor axons rapidly release heparin-binding forms of Neuregulin in response to Schwann cell-derived neurotrophic factors in a dose-dependent manner. Neuregulin release occurs within minutes, is saturable, and occurs from axons that were isolated using a newly designed chamber slide apparatus. Although NGF and glial cell line-derived neurotrophic factor (GDNF) were the most potent neurotrophic factors to release Neuregulin from sensory neurons, GDNF and BDNF were most potent for motor neurons and were the predominant Neuregulin-releasing neurotrophic factors produced by cultured Schwann cells. Comparable levels of Neuregulin could be released at a similar rate from neurons after protein kinase C activation with the phorbol ester, phorbol 12-myristate 13-acetate, which has also been shown to promote the cleavage and release of Neuregulin from its transmembrane precursor. The rapid release of Neuregulin from axons in response to Schwann cell-derived neurotrophic factors may be part of a spatially restricted system of communication at the axoglial interface important for proper peripheral nerve development, function, and repair.
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Neuregulin: an activity-dependent synaptic modulator at the neuromuscular junction.
Journal of Neurocytology, 2003Co-Authors: Jeffrey A. LoebAbstract:Synaptic activity in the form of neurotransmitter release and postsynaptic depolarization is a prime motive force that guides synaptic development throughout the nervous system. The molecular basis of how synaptic activity is converted into structural changes that build and maintain synapses is a key question that has recently become focused on regulatory factors that act on tyrosine kinase receptors on both sides of the synaptic interface. The Neuregulins are such a family of growth and differentiation factors that exist as both membrane-bound and soluble forms through alternatively splicing. Neuregulin functions to promote the local expression of acetylcholine receptors at neuromuscular synapses and therefore has the potential to strengthen specific synaptic connections. Recent evidence suggests that synaptic activity at the neuromuscular junction is coupled to presynaptic Neuregulin release through an indirect mechanism acting through the postsynaptic expression of neurotrophic factors. At early stages of development, this could potentiate the stability of more active synapses. Later in development, heparin-binding forms of Neuregulin accumulate to high levels in the synaptic basal lamina through the developmentally programmed expression of heparan sulfate proteoglycans, thus providing a sustained source of Neuregulin to the most active synapses.
Timothy Vartanian - One of the best experts on this subject based on the ideXlab platform.
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Failure of spinal cord oligodendr4 lacking Neuregulin
2016Co-Authors: Timothy VartanianAbstract:Oligodendrocytes develop from a subpopu- lation of precursor cells within the ventral ventricular zone of the spinal cord. The molecular cues that direct this spatially and temporally restricted event seem to originate in part from structures ventral to and within the spinal cord. Here, we present evidence that the family of ligands termed Neuregulins are necessary for the normal generation of mouse spinal cord oligodendrocytes. Oligodendrocytes mature in spinal cord explants from wild-type mice and mice heterozygotic for a null mutation in the Neuregulin gene (NRG +/-) in a temporal sequence of developmental events that replicates that ob- served in vivo. However, in spinal cord explants derived from mice lacking Neuregulin (NRG -/-), oligodendrocytes fail to develop. Addition of recombinant Neuregulin to spinal cord explants from NRG -/- mice rescues oligodendrocyte de- velopment. In wild-type spinal cord explants, inhibitors of Neuregulin mimic the inhibition of oligodendrocyte develop- ment that occurs in NRG -/- explants. In embryonic mouse spinal cord, Neuregulins are present in motor neurons and the ventral ventricular zone where they likely exert their influence
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Neuregulin: an oligodendrocyte growth factor absent in active multiple sclerosis lesions.
Developmental neuroscience, 2001Co-Authors: Andrea Viehover, Gerald D. Fischbach, Robert H. Miller, Song Kyu Park, Timothy VartanianAbstract:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which results in demyelination and axonal injury. Conventional therapy for MS is immune suppression in the absence of agents that promote neural and glial survival or remyelination. Neuregulins are a family of ligands that exert trophic effects on both neurons and glia. Using mice bearing a null mutation in the Neuregulin gene, here we demonstrate that Neuregulins are necessary for the normal development of oligodendrocytes. In addition, Neuregulins are produced in the normal human CNS by astrocytes as well as neurons. Astrocyte-derived Neuregulin is functionally active in bioassays and exists in secreted and membrane-associated beta-isoforms. In active and chronic active MS lesions, however, the expression of astrocyte Neuregulin is dramatically reduced. The absence of Neuregulin in active MS lesions may contribute to the paucity of remyelination in MS.
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Failure of spinal cord oligodendrocyte development in mice lacking Neuregulin.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Timothy Vartanian, Gerald D. Fischbach, Robert H. MillerAbstract:Oligodendrocytes develop from a subpopulation of precursor cells within the ventral ventricular zone of the spinal cord. The molecular cues that direct this spatially and temporally restricted event seem to originate in part from structures ventral to and within the spinal cord. Here, we present evidence that the family of ligands termed Neuregulins are necessary for the normal generation of mouse spinal cord oligodendrocytes. Oligodendrocytes mature in spinal cord explants from wild-type mice and mice heterozygotic for a null mutation in the Neuregulin gene (NRG +/−) in a temporal sequence of developmental events that replicates that observed in vivo. However, in spinal cord explants derived from mice lacking Neuregulin (NRG −/−), oligodendrocytes fail to develop. Addition of recombinant Neuregulin to spinal cord explants from NRG −/− mice rescues oligodendrocyte development. In wild-type spinal cord explants, inhibitors of Neuregulin mimic the inhibition of oligodendrocyte development that occurs in NRG −/− explants. In embryonic mouse spinal cord, Neuregulins are present in motor neurons and the ventral ventricular zone where they likely exert their influence on early oligodendrocyte precursor cells.
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Axonal Neuregulin Signals Cells of the Oligodendrocyte Lineage through Activation of HER4 and Schwann Cells through HER2 and HER3
Journal of Cell Biology, 1997Co-Authors: Timothy Vartanian, Andrew D. J. Goodearl, Andrea Viehover, Gerald D. FischbachAbstract:We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of Neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor–inducing activity. Three signal transducing transmembrane receptors for Neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite–type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant Neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, Neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique Neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.