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Deepak Srivastava - One of the best experts on this subject based on the ideXlab platform.

  • Image_1_Premature microRNA-1 Expression Causes Hypoplasia of the Cardiac Ventricular Conduction System.tif
    2019
    Co-Authors: Eva Samal, Deepak Srivastava, Yong Zhao, Melissa Evangelista, Giselle Galang, Vasanth Vedantham
    Abstract:

    Mammalian cardiac Purkinje fibers (PFs) are specified from ventricular trabecular myocardium during mid-gestation and undergo limited proliferation before assuming their final form. microRNA-1 (miR-1), a negative regulator of proliferation, is normally expressed in the heart at low levels during the period of PF specification and outgrowth, but expression rises steeply after birth, when myocardial proliferation slows and postnatal cardiac maturation and growth commence. Here, we test whether premature up-regulation and overexpression of miR-1 during the period of PF morphogenesis influences PF development and function. Using a mouse model in which miR-1 is expressed under the control of the Myh6 promoter, we demonstrate that premature miR-1 expression leads to PF hypoplasia that persists into adulthood, and miR-1 TG mice exhibit delayed conduction through the ventricular myocardium beginning at neonatal stages. In addition, miR-1 transgenic embryos showed reduced proliferation within the trabecular myocardium and embryonic ventricular conduction system (VCS), a source of progenitor cells for the PF. This repression of proliferation may be mediated by direct translational inhibition by miR-1 of the cyclin dependent kinase Cdk6, a key regulator of embryonic myocardial proliferation. Our results suggest that altering the timing of miR-1 expression can regulate PF development, findings which have implications for our understanding of conduction system development and disease in humans.

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Journal of Cell Science, 2017
    Co-Authors: Junyi Zhu, Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Zhe Han, Isabelle N King
    Abstract:

    Author(s): Zhu, Jun-yi; Heidersbach, Amy; Kathiriya, Irfan S; Garay, Bayardo I; Ivey, Kathryn N; Srivastava, Deepak; Han, Zhe; King, Isabelle N

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Development, 2017
    Co-Authors: Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Isabelle N King
    Abstract:

    miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4 . Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila . Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like ( Nedd4l ) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1 -mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.

  • microRNA 1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart
    eLife, 2013
    Co-Authors: Amy Heidersbach, Kathryn N Ivey, Chris Saxby, Karen Carvermoore, Yu Huang, Yensin Ang, Pieter J De Jong, Deepak Srivastava
    Abstract:

    microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle-enriched miRNA. Most mammalian genomes contain two copies of miR-1, and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth muscle gene expression network. DOI: http://dx.doi.org/10.7554/eLife.01323.001.

  • serum response factor regulates a muscle specific microRNA that targets hand2 during cardiogenesis
    Nature, 2005
    Co-Authors: Deepak Srivastava, Yong Zhao, Eva Samal
    Abstract:

    Gradients of signalling and transcription factors govern many aspects of embryogenesis, highlighting the need for spatiotemporal control of regulatory protein levels. microRNAs are phylogenetically conserved small RNAs that regulate the translation of target messenger RNAs, providing a mechanism for protein dose regulation. Here we show that microRNA-1-1 (miR-1-1) and miR-1-2 are specifically expressed in cardiac and skeletal muscle precursor cells. We found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2. Correspondingly, excess miR-1 in the developing heart leads to a decreased pool of proliferating ventricular cardiomyocytes. Using a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility, we show that Hand2, a transcription factor that promotes ventricular cardiomyocyte expansion, is a target of miR-1. This work suggests that miR-1 genes titrate the effects of critical cardiac regulatory proteins to control the balance between differentiation and proliferation during cardiogenesis.

Xi-long Zheng - One of the best experts on this subject based on the ideXlab platform.

  • induction of microRNA 1 by myocardin in smooth muscle cells inhibits cell proliferation
    Arteriosclerosis Thrombosis and Vascular Biology, 2011
    Co-Authors: Jie Chen, Sarvan Kumar Radhakrishnan, Zhanpeng Huang, Elisabeth P C Kilsdonk, Yulan Jiang, Jingjing Li, Xi-long Zheng
    Abstract:

    Objective— Myocardin is a cardiac- and smooth muscle–specific transcription co-factor that potently activates the expression of downstream target genes. Previously, we demonstrated that overexpression of myocardin inhibited the proliferation of smooth muscle cells (SMCs). Recently, myocardin was reported to induce the expression of microRNA-1 (miR-1) in cardiomyocytes. In this study, we investigated whether myocardin induces miR-1 expression to mediate its inhibitory effects on SMC proliferation. Methods and Results— Using tetracycline-regulated expression (T-REx) inducible system expressing myocardin in human vascular SMCs, we found that overexpression of myocardin resulted in significant induction of miR-1 expression and inhibition of SMC proliferation, which was reversed by miR-1 inhibitors. Consistently, introduction of miR-1 into SMCs inhibited their proliferation. We isolated spindle-shaped and epithelioid human SMCs and demonstrated that spindle-shaped SMCs were more differentiated and less proliferative. Correspondingly, spindle-shaped SMCs had significantly higher expression levels of both myocardin and miR-1 than epithelioid SMCs. We identified Pim-1, a serine/threonine kinase, as a target gene for miR-1 in SMCs. Western blot and luciferase reporter assays further confirmed that miR-1 targeted Pim-1 directly. Furthermore, neointimal lesions of mouse carotid arteries displayed downregulation of myocardin and miR-1 with upregulation of Pim-1. Conclusion— Our data demonstrate that miR-1 participates in myocardin-dependent of SMC proliferation inhibition.

  • microRNA 1 inhibits myocardin induced contractility of human vascular smooth muscle cells
    Journal of Cellular Physiology, 2010
    Co-Authors: Yulan Jiang, Xi-long Zheng
    Abstract:

    Myocardin, a cofactor of serum response factor (SRF), specifically induces the expression of contractile proteins to promote differentiation and contractile phenotype of smooth muscle cells (SMCs). SRF directly induces the transcription of microRNA-1 (miR-1) in cardiac and skeletal muscle precursor cells and miR-1 promotes the skeletal muscle differentiation and modulates cardiac hypertrophy. We aimed to examine whether miR-1 plays a role in the regulation of smooth muscle contractility. We found that miR-1 expression was induced by myocardin overexpression in human aortic SMCs. In a collagen lattice contraction assay using SMCs harboring a doxycycline-inducible expression system for myocardin, we found that myocardin expression increased the contractility of SMCs, which was significantly inhibited by exogenous miR-1. Our further studies revealed that exogenous miR-1, which did not affect myocardin or SRF expression, suppressed the expression of contractile proteins, such as α-SMA and SM22, and impaired the actin cytoskeletal organization. Taken together, our results have revealed that myocardin induces miR-1 expression, which represses the expression of contractile proteins and thereby inhibits the contractility of SMCs. Therefore, our findings suggest a role of miR-1 in the negative feedback loop in the regulation of contractility induced by myocardin. J. Cell. Physiol. 225: 506–511, 2010. © 2010 Wiley-Liss, Inc.

  • microRNA 1 inhibits myocardin induced contractility of human vascular smooth muscle cells
    Journal of Cellular Physiology, 2010
    Co-Authors: Yulan Jiang, Xi-long Zheng, Hao Yin
    Abstract:

    Myocardin, a cofactor of serum response factor (SRF), specifically induces the expression of contractile proteins to promote differentiation and contractile phenotype of smooth muscle cells (SMCs). SRF directly induces the transcription of microRNA-1 (miR-1) in cardiac and skeletal muscle precursor cells and miR-1 promotes the skeletal muscle differentiation and modulates cardiac hypertrophy. We aimed to examine whether miR-1 plays a role in the regulation of smooth muscle contractility. We found that miR-1 expression was induced by myocardin overexpression in human aortic SMCs. In a collagen lattice contraction assay using SMCs harboring a doxycycline-inducible expression system for myocardin, we found that myocardin expression increased the contractility of SMCs, which was significantly inhibited by exogenous miR-1. Our further studies revealed that exogenous miR-1, which did not affect myocardin or SRF expression, suppressed the expression of contractile proteins, such as alpha-SMA and SM22, and impaired the actin cytoskeletal organization. Taken together, our results have revealed that myocardin induces miR-1 expression, which represses the expression of contractile proteins and thereby inhibits the contractility of SMCs. Therefore, our findings suggest a role of miR-1 in the negative feedback loop in the regulation of contractility induced by myocardin.

Isabelle N King - One of the best experts on this subject based on the ideXlab platform.

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Journal of Cell Science, 2017
    Co-Authors: Junyi Zhu, Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Zhe Han, Isabelle N King
    Abstract:

    Author(s): Zhu, Jun-yi; Heidersbach, Amy; Kathiriya, Irfan S; Garay, Bayardo I; Ivey, Kathryn N; Srivastava, Deepak; Han, Zhe; King, Isabelle N

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Development, 2017
    Co-Authors: Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Isabelle N King
    Abstract:

    miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4 . Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila . Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like ( Nedd4l ) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1 -mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.

Amy Heidersbach - One of the best experts on this subject based on the ideXlab platform.

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Journal of Cell Science, 2017
    Co-Authors: Junyi Zhu, Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Zhe Han, Isabelle N King
    Abstract:

    Author(s): Zhu, Jun-yi; Heidersbach, Amy; Kathiriya, Irfan S; Garay, Bayardo I; Ivey, Kathryn N; Srivastava, Deepak; Han, Zhe; King, Isabelle N

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Development, 2017
    Co-Authors: Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Isabelle N King
    Abstract:

    miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4 . Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila . Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like ( Nedd4l ) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1 -mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.

  • microRNA 1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart
    eLife, 2013
    Co-Authors: Amy Heidersbach, Kathryn N Ivey, Chris Saxby, Karen Carvermoore, Yu Huang, Yensin Ang, Pieter J De Jong, Deepak Srivastava
    Abstract:

    microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle-enriched miRNA. Most mammalian genomes contain two copies of miR-1, and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth muscle gene expression network. DOI: http://dx.doi.org/10.7554/eLife.01323.001.

Kathryn N Ivey - One of the best experts on this subject based on the ideXlab platform.

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Journal of Cell Science, 2017
    Co-Authors: Junyi Zhu, Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Zhe Han, Isabelle N King
    Abstract:

    Author(s): Zhu, Jun-yi; Heidersbach, Amy; Kathiriya, Irfan S; Garay, Bayardo I; Ivey, Kathryn N; Srivastava, Deepak; Han, Zhe; King, Isabelle N

  • the e3 ubiquitin ligase nedd4 nedd4l is directly regulated by microRNA 1
    Development, 2017
    Co-Authors: Amy Heidersbach, Irfan S Kathiriya, Bayardo I Garay, Kathryn N Ivey, Deepak Srivastava, Isabelle N King
    Abstract:

    miR-1 is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of Drosophila miR-1 produces defects in somatic muscle and embryonic heart development, which have been partly attributed to miR-1 directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of miR-1 in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential miR-1 targets revealed that miR-1 directly regulates the 3′UTR of the E3 ubiquitin ligase Nedd4 . Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Drosophila . Larval fly hearts overexpressing miR-1 have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that miR-1 and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between miR-1 and the mammalian ortholog Nedd4-like ( Nedd4l ) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, miR-1 -mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.

  • microRNA 1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart
    eLife, 2013
    Co-Authors: Amy Heidersbach, Kathryn N Ivey, Chris Saxby, Karen Carvermoore, Yu Huang, Yensin Ang, Pieter J De Jong, Deepak Srivastava
    Abstract:

    microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle-enriched miRNA. Most mammalian genomes contain two copies of miR-1, and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth muscle gene expression network. DOI: http://dx.doi.org/10.7554/eLife.01323.001.