The Experts below are selected from a list of 48813 Experts worldwide ranked by ideXlab platform
Woanyuh Tarn - One of the best experts on this subject based on the ideXlab platform.
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the dead box rna helicase ddx3 associates with export messenger Ribonucleoproteins as well astip associated protein and participates in translational control
Molecular Biology of the Cell, 2008Co-Authors: Woanyuh TarnAbstract:Nuclear export of mRNA is tightly linked to transcription, nuclear mRNA processing, and subsequent maturation in the cytoplasm. Tip-associated protein (TAP) is the major nuclear mRNA export receptor, and it acts coordinately with various factors involved in mRNA expression. We screened for protein factors that associate with TAP and identified several candidates, including RNA helicase DDX3. We demonstrate that DDX3 directly interacts with TAP and that its association with TAP as well as mRNA ribonucleoprotein complexes may occur in the nucleus. Depletion of TAP resulted in nuclear accumulation of DDX3, suggesting that DDX3 is, at least in part, exported along with messenger Ribonucleoproteins to the cytoplasm via the TAP-mediated pathway. Moreover, the observation that DDX3 localizes transiently in cytoplasmic stress granules under cell stress conditions suggests a role for DDX3 in translational control. Indeed, DDX3 associates with translation initiation complexes. However, DDX3 is probably not critical for general mRNA translation but may instead promote efficient translation of mRNAs containing a long or structured 5′ untranslated region. Given that the DDX3 RNA helicase activity is essential for its involvement in translation, we suggest that DDX3 facilitates translation by resolving secondary structures of the 5′-untranslated region in mRNAs during ribosome scanning.
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the dead box rna helicase ddx3 associates with export messenger Ribonucleoproteins as well as tip associated protein and participates in translational control
Molecular Biology of the Cell, 2008Co-Authors: Mingchih Lai, Woanyuh Tarn, Yanhwa Wu LeeAbstract:Nuclear export of mRNA is tightly linked to transcription, nuclear mRNA processing, and subsequent maturation in the cytoplasm. Tip-associated protein (TAP) is the major nuclear mRNA export receptor, and it acts coordinately with various factors involved in mRNA expression. We screened for protein factors that associate with TAP and identified several candidates, including RNA helicase DDX3. We demonstrate that DDX3 directly interacts with TAP and that its association with TAP as well as mRNA ribonucleoprotein complexes may occur in the nucleus. Depletion of TAP resulted in nuclear accumulation of DDX3, suggesting that DDX3 is, at least in part, exported along with messenger Ribonucleoproteins to the cytoplasm via the TAP-mediated pathway. Moreover, the observation that DDX3 localizes transiently in cytoplasmic stress granules under cell stress conditions suggests a role for DDX3 in translational control. Indeed, DDX3 associates with translation initiation complexes. However, DDX3 is probably not critical for general mRNA translation but may instead promote efficient translation of mRNAs containing a long or structured 5' untranslated region. Given that the DDX3 RNA helicase activity is essential for its involvement in translation, we suggest that DDX3 facilitates translation by resolving secondary structures of the 5'-untranslated region in mRNAs during ribosome scanning.
Christine E Beattie - One of the best experts on this subject based on the ideXlab platform.
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spinal muscular atrophy why do low levels of survival motor neuron protein make motor neurons sick
Nature Reviews Neuroscience, 2009Co-Authors: Arthur H M Burghes, Christine E BeattieAbstract:Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear Ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.
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Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?
Nature Reviews Neuroscience, 2009Co-Authors: Arthur H M Burghes, Christine E BeattieAbstract:Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene ( SMN1 ), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear Ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA. Spinal muscular atrophy (SMA) is caused by reduced amounts of the ubiquitously expressed survival motor neuron protein (SMN). SMN functions in RNA metabolism, but the question of which aspect of its function is disrupted to give a motor neuron disease remains unanswered. SMN functions in the assembly of Sm proteins onto small nuclear RNAs (snRNAs) during pre-mRNA splicing. It has been suggested that SMN might have a role in the assembly of other ribonucleoprotein (RNP) complexes. SMA is caused by loss or mutation of SMN1 and retention of SMN2 ,leading to low SMN levels. Proteins that carry mild missense mutations complement SMN2 to restore assembly activity and give a mild phenotype. Loss of SMN in all species results in lethality, indicating that SMN has an essential function. Animal models of SMA can be created by reducing the levels of SMN. It has been proposed that reduction of SMN levels results in an alteration of the small nuclear ribonucleoprotein (snRNP) profile. This is supported by the correlation between snRNP assembly activity and SMA severity in mice; however, a clear indication of the downstream target genes that are affected is currently lacking. SMN is found in axons of cultured cells, and a second hypothesis suggests that altered mRNA transport in axons may contribute to SMA. However, a clear indication of what SMN function is disrupted to alter mRNA transport is lacking. SMN functions in the assembly of RNPs, but it remains unresolved whether it is an axonal or an snRNP component that is disrupted in SMA. Experiments showing a clear suppression of the phenotype by manipulating a particular pathway could be used to demonstrate the crucial pathway in SMA. How a reduction in the level of a ubiquitously expressed protein, SMN, causes the motor neuron–specific deficits that characterize spinal muscular atrophy is unknown. Burghes and Beattie discuss the function of SMN and the debate concerning the crucial pathways disrupted in SMA.
Arthur H M Burghes - One of the best experts on this subject based on the ideXlab platform.
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spinal muscular atrophy why do low levels of survival motor neuron protein make motor neurons sick
Nature Reviews Neuroscience, 2009Co-Authors: Arthur H M Burghes, Christine E BeattieAbstract:Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear Ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.
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Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?
Nature Reviews Neuroscience, 2009Co-Authors: Arthur H M Burghes, Christine E BeattieAbstract:Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene ( SMN1 ), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear Ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA. Spinal muscular atrophy (SMA) is caused by reduced amounts of the ubiquitously expressed survival motor neuron protein (SMN). SMN functions in RNA metabolism, but the question of which aspect of its function is disrupted to give a motor neuron disease remains unanswered. SMN functions in the assembly of Sm proteins onto small nuclear RNAs (snRNAs) during pre-mRNA splicing. It has been suggested that SMN might have a role in the assembly of other ribonucleoprotein (RNP) complexes. SMA is caused by loss or mutation of SMN1 and retention of SMN2 ,leading to low SMN levels. Proteins that carry mild missense mutations complement SMN2 to restore assembly activity and give a mild phenotype. Loss of SMN in all species results in lethality, indicating that SMN has an essential function. Animal models of SMA can be created by reducing the levels of SMN. It has been proposed that reduction of SMN levels results in an alteration of the small nuclear ribonucleoprotein (snRNP) profile. This is supported by the correlation between snRNP assembly activity and SMA severity in mice; however, a clear indication of the downstream target genes that are affected is currently lacking. SMN is found in axons of cultured cells, and a second hypothesis suggests that altered mRNA transport in axons may contribute to SMA. However, a clear indication of what SMN function is disrupted to alter mRNA transport is lacking. SMN functions in the assembly of RNPs, but it remains unresolved whether it is an axonal or an snRNP component that is disrupted in SMA. Experiments showing a clear suppression of the phenotype by manipulating a particular pathway could be used to demonstrate the crucial pathway in SMA. How a reduction in the level of a ubiquitously expressed protein, SMN, causes the motor neuron–specific deficits that characterize spinal muscular atrophy is unknown. Burghes and Beattie discuss the function of SMN and the debate concerning the crucial pathways disrupted in SMA.
Wenjie Wang - One of the best experts on this subject based on the ideXlab platform.
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efficient in vivo gene editing using Ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Wenbo Wu, Zhiwei Lu, Fei Li, Wenjie Wang, Nannan Qian, Jinzhi Duan, Yu Zhang, Fengchao Wang, Ting ChenAbstract:The prokaryotic CRISPR/Cas9 system has recently emerged as a powerful tool for genome editing in mammalian cells with the potential to bring curative therapies to patients with genetic diseases. However, efficient in vivo delivery of this genome editing machinery and indeed the very feasibility of using these techniques in vivo remain challenging for most tissue types. Here, we show that nonreplicable Cas9/sgRNA Ribonucleoproteins can be used to correct genetic defects in skin stem cells of postnatal recessive dystrophic epidermolysis bullosa (RDEB) mice. We developed a method to locally deliver Cas9/sgRNA Ribonucleoproteins into the skin of postnatal mice. This method results in rapid gene editing in epidermal stem cells. Using this method, we show that Cas9/sgRNA Ribonucleoproteins efficiently excise exon80, which covers the point mutation in our RDEB mouse model, and thus restores the correct localization of the collagen VII protein in vivo. The skin blistering phenotype is also significantly ameliorated after treatment. This study provides an in vivo gene correction strategy using Ribonucleoproteins as curative treatment for genetic diseases in skin and potentially in other somatic tissues.
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efficient in vivo gene editing using Ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Wenjie Wang, Yu Zhang, Fengchao Wang, Nanna Qia, Jinzhi Dua, Ting CheAbstract:The prokaryotic CRISPR/Cas9 system has recently emerged as a powerful tool for genome editing in mammalian cells with the potential to bring curative therapies to patients with genetic diseases. However, efficient in vivo delivery of this genome editing machinery and indeed the very feasibility of using these techniques in vivo remain challenging for most tissue types. Here, we show that nonreplicable Cas9/sgRNA Ribonucleoproteins can be used to correct genetic defects in skin stem cells of postnatal recessive dystrophic epidermolysis bullosa (RDEB) mice. We developed a method to locally deliver Cas9/sgRNA Ribonucleoproteins into the skin of postnatal mice. This method results in rapid gene editing in epidermal stem cells. Using this method, we show that Cas9/sgRNA Ribonucleoproteins efficiently excise exon80, which covers the point mutation in our RDEB mouse model, and thus restores the correct localization of the collagen VII protein in vivo. The skin blistering phenotype is also significantly ameliorated after treatment. This study provides an in vivo gene correction strategy using Ribonucleoproteins as curative treatment for genetic diseases in skin and potentially in other somatic tissues.
Ting Chen - One of the best experts on this subject based on the ideXlab platform.
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efficient in vivo gene editing using Ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Wenbo Wu, Zhiwei Lu, Fei Li, Wenjie Wang, Nannan Qian, Jinzhi Duan, Yu Zhang, Fengchao Wang, Ting ChenAbstract:The prokaryotic CRISPR/Cas9 system has recently emerged as a powerful tool for genome editing in mammalian cells with the potential to bring curative therapies to patients with genetic diseases. However, efficient in vivo delivery of this genome editing machinery and indeed the very feasibility of using these techniques in vivo remain challenging for most tissue types. Here, we show that nonreplicable Cas9/sgRNA Ribonucleoproteins can be used to correct genetic defects in skin stem cells of postnatal recessive dystrophic epidermolysis bullosa (RDEB) mice. We developed a method to locally deliver Cas9/sgRNA Ribonucleoproteins into the skin of postnatal mice. This method results in rapid gene editing in epidermal stem cells. Using this method, we show that Cas9/sgRNA Ribonucleoproteins efficiently excise exon80, which covers the point mutation in our RDEB mouse model, and thus restores the correct localization of the collagen VII protein in vivo. The skin blistering phenotype is also significantly ameliorated after treatment. This study provides an in vivo gene correction strategy using Ribonucleoproteins as curative treatment for genetic diseases in skin and potentially in other somatic tissues.
