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Urban Lendahl - One of the best experts on this subject based on the ideXlab platform.
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YB-1 Acts as a Ligand for Notch-3 Receptors and Modulates Receptor Activation
The Journal of biological chemistry, 2009Co-Authors: Thomas Rauen, Sonja Djudjaj, Ute Raffetseder, Björn C. Frye, Philipp J.t. Mühlenberg, Frank Eitner, Urban Lendahl, Jürgen Bernhagen, Steven Dooley, Peter R. MertensAbstract:Y-box (YB) protein-1 is secreted by mesangial and immune cells after cytokine challenge, but extracellular functions are unknown. Here, we demonstrate that extracellular YB-1 associates with outer cell membrane components and interacts with extracellular Notch-3 receptor domains. The interaction appears to be specific for Notch-3, as YB-1-green fluorescent protein binds to the extracellular domains and full-length forms of Notch-3 but not to Notch-1. YB-1-green fluorescent protein and Notch-3 proteins co-localize at cell membranes, and extracellular YB-1 activates Notch-3 signaling, resulting in nuclear translocation of the Notch-3 intracellular domain and up-regulation of Notch target genes. The YB-1/Notch-3 interaction may be of particular relevance for inflammatory mesangioproliferative disease, as both proteins co-localize in an experimental nephritis model and receptor activation temporally and spatially correlates with YB-1 expression.
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a cadasil mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand induced signaling
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Helena Karlström, Urban Lendahl, Paul Beatus, Karin Dannaeus, Gavin Chapman, Johan LundkvistAbstract:Notch receptors are single transmembrane receptors that contain a large number of epidermal growth factor-like repeats (EGF repeats) in their extracellular domains. Mutations in the EGF repeats of the human Notch 3 receptor lead to the vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The vast majority of CADASIL mutations are missense mutations removing or inserting cysteine residues in the EGF repeats, but it is not yet clear whether these mutations primarily affect receptor trafficking, maturation, and/or signaling. To address this issue, we have generated and analyzed stable cell lines expressing either wild-type murine Notch 3 (mNotch 3) or the mutant mNotch 3R142C, which corresponds to the prevalent CADASIL form of Notch 3, Notch 3R141C in humans. We find that a lower proportion of mNotch 3R142C is expressed in the site 1-cleaved configuration, and that reduced amounts of mNotch 3R142C appear at the cell surface, as compared with wild-type mNotch 3. This observation is accompanied by a higher propensity for mNotch 3R142C to form intracellular aggregates, which may be a result of increased accumulation or slowed transport in the secretory pathway. In contrast to the impaired cell surface expression, mNotch 3R142C signals equally well in response to Delta 1 and Jagged 1 as wild-type mNotch 3. Taken together, these data suggest that trafficking and localization rather than signaling of mNotch 3 are affected in mNotch 3R142C.
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Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL.
Experimental cell research, 2002Co-Authors: Nilima Prakash, Emil M. Hansson, Christer Betsholtz, Thimios A. Mitsiadis, Urban LendahlAbstract:Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain. Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus. Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3. The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.
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the Notch 3 intracellular domain represses Notch 1 mediated activation through hairy enhancer of split hes promoters
Development, 1999Co-Authors: Paul Beatus, Johan Lundkvist, Camilla Öberg, Urban LendahlAbstract:The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.
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The Notch 3 intracellular domain represses Notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters
Development (Cambridge England), 1999Co-Authors: Paul Beatus, Johan Lundkvist, Camilla Öberg, Urban LendahlAbstract:The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.
Cenk Ayata - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome Mutations Increase Susceptibility to Spreading Depression
Annals of neurology, 2011Co-Authors: Katharina Eikermann-haerter, Izumi Yuzawa, Ergin Dilekoz, Michael A. Moskowitz, Cenk AyataAbstract:Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by Notch3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome Mutations Increase Susceptibility to Spreading Depression
Annals of neurology, 2011Co-Authors: Katharina Eikermann-haerter, Izumi Yuzawa, Ergin Dilekoz, Michael A. Moskowitz, Anne Joutel, Cenk AyataAbstract:Migraine with aura is often the first manifestation of CADASIL syndrome, a disorder caused by Notch3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression, the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
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Linking Notch signaling to ischemic stroke
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Joseph F. Arboleda-velasquez, Cenk Ayata, Zhipeng Zhou, Hwa Kyoung Shin, Angeliki Louvi, Hyung-hwan Kim, Sean I. Savitz, James K. Liao, Salvatore Salomone, Michael A. MoskowitzAbstract:Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
Michael A. Moskowitz - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome Mutations Increase Susceptibility to Spreading Depression
Annals of neurology, 2011Co-Authors: Katharina Eikermann-haerter, Izumi Yuzawa, Ergin Dilekoz, Michael A. Moskowitz, Cenk AyataAbstract:Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by Notch3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome Mutations Increase Susceptibility to Spreading Depression
Annals of neurology, 2011Co-Authors: Katharina Eikermann-haerter, Izumi Yuzawa, Ergin Dilekoz, Michael A. Moskowitz, Anne Joutel, Cenk AyataAbstract:Migraine with aura is often the first manifestation of CADASIL syndrome, a disorder caused by Notch3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression, the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
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Linking Notch signaling to ischemic stroke
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Joseph F. Arboleda-velasquez, Cenk Ayata, Zhipeng Zhou, Hwa Kyoung Shin, Angeliki Louvi, Hyung-hwan Kim, Sean I. Savitz, James K. Liao, Salvatore Salomone, Michael A. MoskowitzAbstract:Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
Paul Beatus - One of the best experts on this subject based on the ideXlab platform.
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Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype.
Genesis (New York N.Y. : 2000), 2005Co-Authors: Johan Lundkvist, Emil M. Hansson, Shunwei Zhu, Petra Schweinhardt, Qing Miao, Paul Beatus, Karin Dannaeus, Helena Karlström, Clas B. Johansson, Matti ViitanenAbstract:CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, MIM 125310) is a genetic vascular dementia disease that is linked to missense mutations, small in-frame deletions, and splice site mutations in the human Notch 3 gene. Here we describe the generation of a mouse knockin model for one of the most prevalent CADASIL mutations, an arginine to cysteine transition at position 141, R141C, which corresponds to mutation R142C in mouse Notch 3. CADASIL(R142C) mice show no apparent CADASIL-like phenotype after histological and MRI analysis. The Notch 3 (R142C) receptor is processed normally and does not appear to accumulate the ectodomain, which has been observed in CADASIL patients. We discuss possible reasons for the different outcomes of the same germline CADASIL mutation in mice and humans.
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a cadasil mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand induced signaling
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Helena Karlström, Urban Lendahl, Paul Beatus, Karin Dannaeus, Gavin Chapman, Johan LundkvistAbstract:Notch receptors are single transmembrane receptors that contain a large number of epidermal growth factor-like repeats (EGF repeats) in their extracellular domains. Mutations in the EGF repeats of the human Notch 3 receptor lead to the vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The vast majority of CADASIL mutations are missense mutations removing or inserting cysteine residues in the EGF repeats, but it is not yet clear whether these mutations primarily affect receptor trafficking, maturation, and/or signaling. To address this issue, we have generated and analyzed stable cell lines expressing either wild-type murine Notch 3 (mNotch 3) or the mutant mNotch 3R142C, which corresponds to the prevalent CADASIL form of Notch 3, Notch 3R141C in humans. We find that a lower proportion of mNotch 3R142C is expressed in the site 1-cleaved configuration, and that reduced amounts of mNotch 3R142C appear at the cell surface, as compared with wild-type mNotch 3. This observation is accompanied by a higher propensity for mNotch 3R142C to form intracellular aggregates, which may be a result of increased accumulation or slowed transport in the secretory pathway. In contrast to the impaired cell surface expression, mNotch 3R142C signals equally well in response to Delta 1 and Jagged 1 as wild-type mNotch 3. Taken together, these data suggest that trafficking and localization rather than signaling of mNotch 3 are affected in mNotch 3R142C.
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the Notch 3 intracellular domain represses Notch 1 mediated activation through hairy enhancer of split hes promoters
Development, 1999Co-Authors: Paul Beatus, Johan Lundkvist, Camilla Öberg, Urban LendahlAbstract:The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.
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The Notch 3 intracellular domain represses Notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters
Development (Cambridge England), 1999Co-Authors: Paul Beatus, Johan Lundkvist, Camilla Öberg, Urban LendahlAbstract:The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.
Peter R. Mertens - One of the best experts on this subject based on the ideXlab platform.
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extracellular yb 1 blockade in experimental nephritis upregulates Notch 3 receptor expression and signaling
Nephron Experimental Nephrology, 2011Co-Authors: Ute Raffetseder, Sonja Djudjaj, Peter Boor, Lydia Hanssen, Thomas Rauen, Björn C. Frye, Tammo Ostendorf, Jurgen Floege, Abdelaziz Ennia, Peter R. MertensAbstract:Background: Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y- box (YB) protein-1 f
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YB-1 Acts as a Ligand for Notch-3 Receptors and Modulates Receptor Activation
The Journal of biological chemistry, 2009Co-Authors: Thomas Rauen, Sonja Djudjaj, Ute Raffetseder, Björn C. Frye, Philipp J.t. Mühlenberg, Frank Eitner, Urban Lendahl, Jürgen Bernhagen, Steven Dooley, Peter R. MertensAbstract:Y-box (YB) protein-1 is secreted by mesangial and immune cells after cytokine challenge, but extracellular functions are unknown. Here, we demonstrate that extracellular YB-1 associates with outer cell membrane components and interacts with extracellular Notch-3 receptor domains. The interaction appears to be specific for Notch-3, as YB-1-green fluorescent protein binds to the extracellular domains and full-length forms of Notch-3 but not to Notch-1. YB-1-green fluorescent protein and Notch-3 proteins co-localize at cell membranes, and extracellular YB-1 activates Notch-3 signaling, resulting in nuclear translocation of the Notch-3 intracellular domain and up-regulation of Notch target genes. The YB-1/Notch-3 interaction may be of particular relevance for inflammatory mesangioproliferative disease, as both proteins co-localize in an experimental nephritis model and receptor activation temporally and spatially correlates with YB-1 expression.
