The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Weichun Lin - One of the best experts on this subject based on the ideXlab platform.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1).
PLoS genetics, 2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic Muscles, leading to Muscle Denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of Muscle Denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1-/-), which lack Schwann cells. We found that Muscle Denervation and neuromuscular synapse loss were prevented in CRD-Nrg1-/-mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes Muscle-specific AChRs in CRD-Nrg1-/-mice also rescued Muscle Denervation. Moreover, genetically ablating Muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued Muscle Denervation and neuromuscular synapse loss in CRD-Nrg1-/-mice. Thus, these genetic manipulations follow a pathway-from presynaptic to postsynaptic, and, ultimately to Muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1-/-Cacnb1-/-or CRD-Nrg1-/-Ryr1-/-mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of Muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that Muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1) - Fig 10
2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:The main findings are illustrated (A). Neuromuscular synapses (NMJs) are normally formed as a tripartite structure including a presynaptic nerve terminal (green), a postsynaptic Muscle (orange) and a Schwann cell (glia, pink). Schwann cells are essential for the formation of the NMJ; in the absence of Schwann cells, nerve terminals withdraw from Muscles, resulting in synapse loss (synapse degeneration) and Muscle Denervation (as shown in CRD-Nrg1−/−mice). These defects are rescued by (1) a blockade of evoked neurotransmitter release (CRD-Nrg1−/−Snap25−/−); (2) a blockade of neurotransmitter synthesis (CRD-Nrg1−/−Chat−/–); (3) a blockade of post-synaptic AChRs (CRD-Nrg1−/−Chrna1−/−); (4) a blockade of Muscle dihydropyridine receptors (CRD-Nrg1−/−Cacnb1−/−); and (5) a blockade of Muscle ryanodine receptor 1 (CRD-Nrg1−/−Ryr1−/−). These genetic rescues reveal a common pathway (B) that ultimately leads to Muscle activity mediated by DHPR/Ryr1. Therefore, a blockade of Muscle activity is the key to rescuing Muscle Denervation/synapse loss in the absence of Schwann cells. Together, these genetic manipulations indicate that the blockade of Muscle activity prevents Muscle Denervation and neuromuscular synapse loss caused by CRD-NRG1 deficiencies in mice.
Yun Liu - One of the best experts on this subject based on the ideXlab platform.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1).
PLoS genetics, 2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic Muscles, leading to Muscle Denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of Muscle Denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1-/-), which lack Schwann cells. We found that Muscle Denervation and neuromuscular synapse loss were prevented in CRD-Nrg1-/-mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes Muscle-specific AChRs in CRD-Nrg1-/-mice also rescued Muscle Denervation. Moreover, genetically ablating Muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued Muscle Denervation and neuromuscular synapse loss in CRD-Nrg1-/-mice. Thus, these genetic manipulations follow a pathway-from presynaptic to postsynaptic, and, ultimately to Muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1-/-Cacnb1-/-or CRD-Nrg1-/-Ryr1-/-mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of Muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that Muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1) - Fig 10
2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:The main findings are illustrated (A). Neuromuscular synapses (NMJs) are normally formed as a tripartite structure including a presynaptic nerve terminal (green), a postsynaptic Muscle (orange) and a Schwann cell (glia, pink). Schwann cells are essential for the formation of the NMJ; in the absence of Schwann cells, nerve terminals withdraw from Muscles, resulting in synapse loss (synapse degeneration) and Muscle Denervation (as shown in CRD-Nrg1−/−mice). These defects are rescued by (1) a blockade of evoked neurotransmitter release (CRD-Nrg1−/−Snap25−/−); (2) a blockade of neurotransmitter synthesis (CRD-Nrg1−/−Chat−/–); (3) a blockade of post-synaptic AChRs (CRD-Nrg1−/−Chrna1−/−); (4) a blockade of Muscle dihydropyridine receptors (CRD-Nrg1−/−Cacnb1−/−); and (5) a blockade of Muscle ryanodine receptor 1 (CRD-Nrg1−/−Ryr1−/−). These genetic rescues reveal a common pathway (B) that ultimately leads to Muscle activity mediated by DHPR/Ryr1. Therefore, a blockade of Muscle activity is the key to rescuing Muscle Denervation/synapse loss in the absence of Schwann cells. Together, these genetic manipulations indicate that the blockade of Muscle activity prevents Muscle Denervation and neuromuscular synapse loss caused by CRD-NRG1 deficiencies in mice.
Bernard J. Jasmin - One of the best experts on this subject based on the ideXlab platform.
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HuR Mediates Changes in the Stability of AChR β-Subunit mRNAs after Skeletal Muscle Denervation.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015Co-Authors: Olivier R. Joassard, Guy Bélanger, Jennifer Karmouch, John A. Lunde, Anu Heidi Shukla, Angèle Chopard, Claire Legay, Bernard J. JasminAbstract:Acetylcholine receptors (AChRs) are heteromeric membrane proteins essential for neurotransmission at the neuromuscular junction. Previous work showed that Muscle Denervation increases expression of AChR mRNAs due to transcriptional activation of AChR subunit genes. However, it remains possible that post-transcriptional mechanisms are also involved in controlling the levels of AChR mRNAs following Denervation. We examined whether post-transcriptional events indeed regulate AChR β-subunit mRNAs in response to Denervation. First, in vitro stability assays revealed that the half-life of AChR β-subunit mRNAs was increased in the presence of denervated Muscle protein extracts. A bioinformatics analysis revealed the existence of a conserved AU-rich element (ARE) in the 3′-untranslated region (UTR) of AChR β-subunit mRNA. Furthermore, Denervation of mouse Muscle injected with a luciferase reporter construct containing the AChR β-subunit 3′UTR, caused an increase in luciferase activity. By contrast, mutation of this ARE prevented this increase. We also observed that Denervation increased expression of the RNA-binding protein human antigen R (HuR) and induced its translocation to the cytoplasm. Importantly, HuR binds to endogenous AChR β-subunit transcripts in cultured myotubes and in vivo, and this binding is increased in denervated versus innervated Muscles. Finally, p38 MAPK, a pathway known to activate HuR, was induced following Denervation as a result of MKK3/6 activation and a decrease in MKP-1 expression, thereby leading to an increase in the stability of AChR β-subunit transcripts. Together, these results demonstrate the important contribution of post-transcriptional events in regulating AChR β-subunit mRNAs and point toward a central role for HuR in mediating synaptic gene expression. SIGNIFICANCE STATEMENT Muscle Denervation is a convenient model to examine expression of genes encoding proteins of the neuromuscular junction, especially acetylcholine receptors (AChRs). Despite the accepted model of AChR regulation, which implicates transcriptional mechanisms, it remains plausible that such events cannot fully account for changes in AChR expression following Denervation. We show that Denervation increases expression of the RNA-binding protein HuR, which in turn, causes an increase in the stability of AChR β-subunit mRNAs in denervated Muscle. Our findings demonstrate for the first time the contribution of post-transcriptional events in controlling AChR expression in skeletal Muscle, and points toward a central role for HuR in mediating synaptic development while also paving the way for developing RNA-based therapeutics for neuromuscular diseases.
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HuR mediates changes in the stability of AChR β-Subunit mRNAs after skeletal Muscle Denervation
Journal of Neuroscience, 2015Co-Authors: Olivier R. Joassard, Guy Bélanger, Jennifer Karmouch, John A. Lunde, Anu Heidi Shukla, Angèle Chopard, Claire Legay, Bernard J. JasminAbstract:Acetylcholine receptors (AChRs) are heteromeric membrane proteins essential for neurotransmission at the neuromuscular junction. Previous work showed that Muscle Denervation increases expression of AChR mRNAs due to transcriptional activation of AChR subunit genes. However, it remains possible that post-transcriptional mechanisms are also involved in controlling the levels of AChR mRNAs following Denervation. We examined whether post-transcriptional events indeed regulate AChR β-subunit mRNAs in response to Denervation. First, in vitro stability assays revealed that the half-life of AChR β-subunit mRNAs was increased in the presence of denervated Muscle protein extracts. A bioinformatics analysis revealed the existence of a conserved AU-rich element (ARE) in the 3'-untranslated region (UTR) of AChR β-subunit mRNA. Furthermore, Denervation of mouse Muscle injected with a luciferase reporter construct containing the AChR β-subunit 3'UTR, caused an increase in luciferase activity. By contrast, mutation of this ARE prevented this increase. We also observed that Denervation increased expression of the RNA-binding protein human antigen R (HuR) and induced its translocation to the cytoplasm. Importantly, HuR binds to endogenous AChR β-subunit transcripts in cultured myotubes and in vivo, and this binding is increased in denervated versus innervated Muscles. Finally, p38 MAPK, a pathway known to activate HuR, was induced following Denervation as a result of MKK3/6 activation and a decrease in MKP-1 expression, thereby leading to an increase in the stability of AChR β-subunit transcripts. Together, these results demonstrate the important contribution of post-transcriptional events in regulating AChR β-subunit mRNAs and point toward a central role for HuR in mediating synaptic gene expression.
Kuo-fen Lee - One of the best experts on this subject based on the ideXlab platform.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1).
PLoS genetics, 2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic Muscles, leading to Muscle Denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of Muscle Denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1-/-), which lack Schwann cells. We found that Muscle Denervation and neuromuscular synapse loss were prevented in CRD-Nrg1-/-mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes Muscle-specific AChRs in CRD-Nrg1-/-mice also rescued Muscle Denervation. Moreover, genetically ablating Muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued Muscle Denervation and neuromuscular synapse loss in CRD-Nrg1-/-mice. Thus, these genetic manipulations follow a pathway-from presynaptic to postsynaptic, and, ultimately to Muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1-/-Cacnb1-/-or CRD-Nrg1-/-Ryr1-/-mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of Muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that Muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1) - Fig 10
2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:The main findings are illustrated (A). Neuromuscular synapses (NMJs) are normally formed as a tripartite structure including a presynaptic nerve terminal (green), a postsynaptic Muscle (orange) and a Schwann cell (glia, pink). Schwann cells are essential for the formation of the NMJ; in the absence of Schwann cells, nerve terminals withdraw from Muscles, resulting in synapse loss (synapse degeneration) and Muscle Denervation (as shown in CRD-Nrg1−/−mice). These defects are rescued by (1) a blockade of evoked neurotransmitter release (CRD-Nrg1−/−Snap25−/−); (2) a blockade of neurotransmitter synthesis (CRD-Nrg1−/−Chat−/–); (3) a blockade of post-synaptic AChRs (CRD-Nrg1−/−Chrna1−/−); (4) a blockade of Muscle dihydropyridine receptors (CRD-Nrg1−/−Cacnb1−/−); and (5) a blockade of Muscle ryanodine receptor 1 (CRD-Nrg1−/−Ryr1−/−). These genetic rescues reveal a common pathway (B) that ultimately leads to Muscle activity mediated by DHPR/Ryr1. Therefore, a blockade of Muscle activity is the key to rescuing Muscle Denervation/synapse loss in the absence of Schwann cells. Together, these genetic manipulations indicate that the blockade of Muscle activity prevents Muscle Denervation and neuromuscular synapse loss caused by CRD-NRG1 deficiencies in mice.
Yoshie Sugiura - One of the best experts on this subject based on the ideXlab platform.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1).
PLoS genetics, 2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic Muscles, leading to Muscle Denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of Muscle Denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1-/-), which lack Schwann cells. We found that Muscle Denervation and neuromuscular synapse loss were prevented in CRD-Nrg1-/-mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes Muscle-specific AChRs in CRD-Nrg1-/-mice also rescued Muscle Denervation. Moreover, genetically ablating Muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued Muscle Denervation and neuromuscular synapse loss in CRD-Nrg1-/-mice. Thus, these genetic manipulations follow a pathway-from presynaptic to postsynaptic, and, ultimately to Muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1-/-Cacnb1-/-or CRD-Nrg1-/-Ryr1-/-mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of Muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that Muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.
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Blocking skeletal Muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1) - Fig 10
2019Co-Authors: Yun Liu, Yoshie Sugiura, Fujun Chen, Kuo-fen Lee, Weichun LinAbstract:The main findings are illustrated (A). Neuromuscular synapses (NMJs) are normally formed as a tripartite structure including a presynaptic nerve terminal (green), a postsynaptic Muscle (orange) and a Schwann cell (glia, pink). Schwann cells are essential for the formation of the NMJ; in the absence of Schwann cells, nerve terminals withdraw from Muscles, resulting in synapse loss (synapse degeneration) and Muscle Denervation (as shown in CRD-Nrg1−/−mice). These defects are rescued by (1) a blockade of evoked neurotransmitter release (CRD-Nrg1−/−Snap25−/−); (2) a blockade of neurotransmitter synthesis (CRD-Nrg1−/−Chat−/–); (3) a blockade of post-synaptic AChRs (CRD-Nrg1−/−Chrna1−/−); (4) a blockade of Muscle dihydropyridine receptors (CRD-Nrg1−/−Cacnb1−/−); and (5) a blockade of Muscle ryanodine receptor 1 (CRD-Nrg1−/−Ryr1−/−). These genetic rescues reveal a common pathway (B) that ultimately leads to Muscle activity mediated by DHPR/Ryr1. Therefore, a blockade of Muscle activity is the key to rescuing Muscle Denervation/synapse loss in the absence of Schwann cells. Together, these genetic manipulations indicate that the blockade of Muscle activity prevents Muscle Denervation and neuromuscular synapse loss caused by CRD-NRG1 deficiencies in mice.
