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Pamela J Kennedy,
Jian Feng,
A J Robison,
Ian Maze,
Ana Badimon,
Ezekiell Mouzon,
Dipesh Chaudhury,
Diane M Damez-Werno,
Stephen J Haggarty,
Ming-Hu Han, Rhonda Bassel-Duby,
Eric N Olson,
Eric J Nestler
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ABSTRACT: Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and previous studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part through a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a new mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of therapeutics for cocaine addiction.
Nature Neuroscience 03/2013; · 15.53 Impact Factor
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Young-Jae Nam,
Kunhua Song,
Xiang Luo,
Edward Daniel,
Kaleb Lambeth,
Katherine West,
Joseph A Hill,
J Michael Dimaio,
Linda A Baker, Rhonda Bassel-Duby,
Eric N Olson
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ABSTRACT: Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.
Proceedings of the National Academy of Sciences 03/2013; · 9.68 Impact Factor
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Guo N. Huang,
Jeffrey E. Thatcher,
John McAnally,
Yongli Kong,
Xiaoxia Qi,
Wei Tan,
J. Michael DiMaio,
James F. Amatruda,
Robert D. Gerard,
Joseph A. Hill, Rhonda Bassel-Duby,
Eric N. Olson
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ABSTRACT: The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential
for cardiac development and repair. Injury of the adult heart results in reactivation of a developmental gene program in the
epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic
heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during
heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered
on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced
injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial
activation and heart injury, providing a platform for enhancing cardiac regeneration.
Science 12/2012; 338(6114):1599-1603. · 31.20 Impact Factor
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ABSTRACT: Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome
proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial
biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically
lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid
metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex
that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in
the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and
miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components
of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the
overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention
in obesity and metabolic syndrome.
Proceedings of the National Academy of Sciences 09/2012; 109(38):15330-15335. · 9.68 Impact Factor
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ABSTRACT: Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxi-some proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mito-chondrial biogenesis through stimulation of nuclear hormone recep-tors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mito-chondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hor-mone receptor activity, are repressed by miR-378 and miR-378*, re-spectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miR-NAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome. fatty acid oxidation | adipocytes | mitochondrial CO 2 production M etabolic syndrome is a systemic disorder that includes a spectrum of abnormalities associated with obesity and type II diabetes. Defects in mitochondrial oxidative metabolism of fatty acids have been linked to diet-induced obesity and the de-velopment of insulin resistance in adipose tissue and skeletal muscle (1, 2). Consistent with the observation that mitochondrial dysfunction is a risk factor for the development of metabolic syn-drome, obese individuals have mitochondria with compromised bioenergetic capacity (3–6). Mitochondrial biogenesis, thermogenesis, and glucose and fatty acid metabolism are regulated by peroxisome proliferator-acti-vated receptor γ coactivator 1 (PGC-1), a transcriptional coac-tivator that interacts with a broad range of transcription factors (7, 8). The PGC-1 family member PGC-1β is encoded by the Ppargc1b gene and is preferentially expressed in tissues with relatively high mitochondrial content, including heart, slow skeletal muscle, and brown adipose tissue (BAT) (9). Embedded in the first intron of the Ppargc1b gene are two microRNAs (miRNAs), miR-378 and miR-378*, which originate from a common hairpin RNA precursor (10). MiRNAs are ∼22-nt single-stranded RNAs that mediate the degradation or inhibition of specific target mRNAs (11–13). Ap-proximately one-third of miRNAs are encoded by introns of pro-tein-coding genes, and frequently intronic miRNAs have been found to modulate, either positively or negatively, the same bi-ological processes as the protein encoded by the host gene (14–18). Several miRNAs have been implicated in metabolic homeostasis based on loss-of-function studies in mice (16, 19, 20). MiR-33, encoded by an intron of the sterol regulatory element binding protein gene, has been shown to collaborate with sterol regulatory element binding protein to regulate intracellular cholesterol levels and lipid homeostasis by targeting the adenosine triphosphate-binding cassette transporter A1, a regulator of cellular cholesterol efflux (15). Other miRNAs have been linked to the regulation of glucose metabolism. Silencing of miR-103/107 improves glucose homeostasis and insulin sensitivity in mice (21). Lin28a, which inhibits processing of let-7 miRNA, promotes insulin signaling and confers resistance to high-fat diet (HFD)-induced diabetes (22). Conversely, let-7 overexpression impairs glucose tolerance and reduces insulin secretion in mice (22, 23). We recently reported that pharmacologic inhibition of miR-208a in mice confers resistance to obesity and improves insulin sensitivity (24). The influence of miR-208a on systemic energy homeostasis appears to be mediated, at least in part, by repression of MED13, a component of the Mediator complex that regulates nuclear receptor signaling (24, 25). In the present study, we investigated the functions of miR-378 and miR-378* in mice by deleting these miRNAs, leaving the host gene Ppargc1b intact. We found that mice lacking miR-378 and miR-378* are protected against diet-induced obesity. Previous studies have identified numerous metabolic regulatory proteins as targets for repression by miR-378 and miR-378* (10, 26–28). In addition, we found that carnitine O-acetyltransferase (CRAT), a mitochondrial enzyme involved in fatty acid metabolism (29, 30), and MED13 are repressed by miR-378 and miR-378*, re-spectively. Our findings indicate that miR-378 and miR-378* function to control the overall oxidative capacity of metabolically active tissues during periods of dietary stress. These miRNAs thus serve as potential targets for pharmacologic intervention in obe-sity and metabolic syndrome.
Proceedings of the National Academy of Sciences 09/2012; · 9.68 Impact Factor
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ABSTRACT: Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.
Journal of Neuroscience 08/2012; 32(32):10879-86. · 7.11 Impact Factor
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[show abstract]
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ABSTRACT: Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed under-standing of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.
Journal of Neuroscience. 08/2012;
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Kunhua Song,
Young-Jae Nam,
Xiang Luo,
Xiaoxia Qi,
Wei Tan,
Guo N Huang,
Asha Acharya,
Christopher L Smith,
Michelle D Tallquist,
Eric G Neilson,
Joseph A Hill, Rhonda Bassel-Duby,
Eric N Olson
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ABSTRACT: The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.
Nature 05/2012; 485(7400):599-604. · 36.28 Impact Factor
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ABSTRACT: Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy.
The Journal of clinical investigation 05/2012; 122(6):2054-65. · 15.39 Impact Factor
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ABSTRACT: Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.
Cell 04/2012; 149(3):671-83. · 32.40 Impact Factor
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ABSTRACT: MEF2 (A–D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/ dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function.
PLoS ONE 04/2012; · 4.09 Impact Factor
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Arin B Aurora,
Ahmed I Mahmoud,
Xiang Luo,
Brett A Johnson,
Eva van Rooij,
Satoshi Matsuzaki,
Kenneth M Humphries,
Joseph A Hill, Rhonda Bassel-Duby,
Hesham A Sadek,
Eric N Olson
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ABSTRACT: Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca²⁺ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca²⁺ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca²⁺ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca²⁺ influx; and to repression of several downstream effectors of Ca²⁺ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury.
The Journal of clinical investigation 03/2012; 122(4):1222-32. · 15.39 Impact Factor
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ABSTRACT: Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications.
Proceedings of the National Academy of Sciences 01/2012; 109(5):1649-54. · 9.68 Impact Factor
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Ning Liu,
Svetlana Bezprozvannaya,
John M Shelton,
Madlyn I Frisard,
Matthew W Hulver,
Ryan P McMillan,
Yaru Wu,
Kevin A Voelker,
Robert W Grange,
James A Richardson, Rhonda Bassel-Duby,
Eric N Olson
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ABSTRACT: MicroRNAs modulate cellular phenotypes by inhibiting expression of mRNA targets. In this study, we have shown that the muscle-specific microRNAs miR-133a-1 and miR-133a-2 are essential for multiple facets of skeletal muscle function and homeostasis in mice. Mice with genetic deletions of miR-133a-1 and miR-133a-2 developed adult-onset centronuclear myopathy in type II (fast-twitch) myofibers, accompanied by impaired mitochondrial function, fast-to-slow myofiber conversion, and disarray of muscle triads (sites of excitation- contraction coupling). These abnormalities mimicked human centronuclear myopathies and could be ascribed, at least in part, to dysregulation of the miR-133a target mRNA that encodes dynamin 2, a GTPase implicated in human centronuclear myopathy. Our findings reveal an essential role for miR-133a in the maintenance of adult skeletal muscle structure, function, bioenergetics, and myofiber identity; they also identify a potential modulator of centronuclear myopathies.
The Journal of clinical investigation 07/2011; 121(8):3258-68. · 15.39 Impact Factor
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ABSTRACT: In response to physiological stimuli, skeletal muscle alters its myofiber composition to significantly affect muscle performance and metabolism. This process requires concerted regulation of myofiber-specific isoforms of sarcomeric and calcium regulatory proteins that couple action potentials to the generation of contractile force. Here, we identify Sox6 as a fast myofiber-enriched repressor of slow muscle gene expression in vivo. Mice lacking Sox6 specifically in skeletal muscle have an increased number of slow myofibers, elevated mitochondrial activity, and exhibit down-regulation of the fast myofiber gene program, resulting in enhanced muscular endurance. In addition, microarray profiling of Sox6 knockout muscle revealed extensive muscle fiber-type remodeling, and identified numerous genes that display distinctive fiber-type enrichment. Sox6 directly represses the transcription of slow myofiber-enriched genes by binding to conserved cis-regulatory elements. These results identify Sox6 as a robust regulator of muscle contractile phenotype and metabolism, and elucidate a mechanism by which functionally related muscle fiber-type specific gene isoforms are collectively controlled.
Proceedings of the National Academy of Sciences 06/2011; 108(25):10196-201. · 9.68 Impact Factor
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ABSTRACT: The Hippo signaling pathway regulates growth of the heart and other tissues. Hippo pathway kinases influence the activity of various targets, including the transcriptional coactivator Yap, but the specific role of Yap in heart growth has not been investigated. We show that Yap is necessary and sufficient for embryonic cardiac growth in mice. Deletion of Yap in the embryonic mouse heart impeded cardiomyocyte proliferation, causing myocardial hypoplasia and lethality at embryonic stage 10.5. Conversely, forced expression of a constitutively active form of Yap in the embryonic heart increased cardiomyocyte number and heart size. Yap activated the insulin-like growth factor (IGF) signaling pathway in cardiomyocytes, resulting in inactivation of glycogen synthase kinase 3β, which led to increased abundance of β-catenin, a positive regulator of cardiac growth. Our results point to Yap as a critical downstream effector of the Hippo pathway in the control of cardiomyocyte proliferation and a nexus for coupling the IGF, Wnt, and Hippo signaling pathways with the developmental program for heart growth.
Science Signaling 01/2011; 4(196):ra70. · 7.50 Impact Factor
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Viviana Moresi,
Andrew H Williams,
Eric Meadows,
Jesse M Flynn,
Matthew J Potthoff,
John McAnally,
John M Shelton,
Johannes Backs,
William H Klein,
James A Richardson, Rhonda Bassel-Duby,
Eric N Olson
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ABSTRACT: Maintenance of skeletal muscle structure and function requires innervation by motor neurons, such that denervation causes muscle atrophy. We show that myogenin, an essential regulator of muscle development, controls neurogenic atrophy. Myogenin is upregulated in skeletal muscle following denervation and regulates expression of the E3 ubiquitin ligases MuRF1 and atrogin-1, which promote muscle proteolysis and atrophy. Deletion of myogenin from adult mice diminishes expression of MuRF1 and atrogin-1 in denervated muscle and confers resistance to atrophy. Mice lacking histone deacetylases (HDACs) 4 and 5 in skeletal muscle fail to upregulate myogenin and also preserve muscle mass following denervation. Conversely, forced expression of myogenin in skeletal muscle of HDAC mutant mice restores muscle atrophy following denervation. Thus, myogenin plays a dual role as both a regulator of muscle development and an inducer of neurogenic atrophy. These findings reveal a specific pathway for muscle wasting and potential therapeutic targets for this disorder.
Cell 10/2010; 143(1):35-45. · 32.40 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related deaths in the world, and non-small-cell lung cancer (NSCLC) accounts for 80% of cases. MicroRNA-21 (miR-21) expression is increased and predicts poor survival in NSCLC. Although miR-21 function has been studied in vitro with cancer cell lines, the role of miR-21 in tumor development in vivo is unknown. We utilize transgenic mice with loss-of-function and gain-of-function miR-21 alleles combined with a model of NSCLC to determine the role of miR-21 in lung cancer. We show that overexpression of miR-21 enhances tumorigenesis and that genetic deletion of miR-21 partially protects against tumor formation. MiR-21 drives tumorigenesis through inhibition of negative regulators of the Ras/MEK/ERK pathway and inhibition of apoptosis.
Cancer cell 09/2010; 18(3):282-93. · 25.29 Impact Factor
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ABSTRACT: Piwi-interacting RNAs (piRNAs) comprise a broad class of small noncoding RNAs that function as an endogenous defense system against transposable elements. Here we show that the putative DExD-box helicase MOV10-like-1 (MOV10L1) is essential for silencing retrotransposons in the mouse male germline. Mov10l1 is specifically expressed in germ cells with increasing expression from gonocytes/type A spermatogonia to pachytene spermatocytes. Primary spermatocytes of Mov10l1(-/-) mice show activation of LTR and LINE-1 retrotransposons, followed by cell death, causing male infertility and a complete block of spermatogenesis at early prophase of meiosis I. Despite the early expression of Mov10l1, germline stem cell maintenance appears unaffected in Mov10l1(-/-) mice. MOV10L1 interacts with the Piwi proteins MILI and MIWI. MOV10L1 also interacts with heat shock 70-kDa protein 2 (HSPA2), a testis-enriched chaperone expressed in pachytene spermatocytes and also essential for male fertility. These studies reveal a crucial role of MOV10L1 in male fertility and piRNA-directed retrotransposon silencing in male germ cells and suggest that MOV10L1 functions as a key component of a safeguard mechanism for the genetic information in male germ cells of mammals.
Proceedings of the National Academy of Sciences 06/2010; 107(26):11847-52. · 9.68 Impact Factor
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ABSTRACT: We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.
Multiple cellular events that occur during pathological remodeling of the failing ventricle are implicated in the genesis of ventricular tachycardia (VT), including interstitial fibrosis. Recent studies suggest that ventricular fibrosis is reversible, and current anti-remodeling therapies attenuate ventricular fibrosis. However, the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium is currently not well defined.
Class II histone deacetylases (HDACs) have been implicated in promoting collagen biosynthesis. As these enzymes are inhibited by protein kinase D1 (PKD1), we studied mice with cardiomyocyte-specific transgenic over-expression of a constitutively active mutant of PKD1 (caPKD). caPKD mice were compared with animals in which cardiomyopathy was induced by severe thoracic aortic banding (sTAB). Hearts were analyzed by echocardiographic and electrocardiographic means. Interstitial fibrosis was assessed by histology and quantified biochemically. Ventricular arrhythmias were induced by closed-chest, intracardiac pacing.
Similar degrees of hypertrophic growth, systolic dysfunction and mortality were observed in the two models. In sTAB mice, robust ventricular fibrosis was readily detected, but myocardial collagen content was significantly reduced in caPKD mice. As expected, VT was readily inducible by programmed stimulation in sTAB mice and VT was less inducible in caPKD mice. Surprisingly, episodes of VT manifested longer cycle lengths and longer duration in caPKD mice.
Attenuated ventricular fibrosis is associated with reduced VT inducibility, increased VT duration, and significantly longer arrhythmia cycle length.
Journal of Cardiovascular Electrophysiology 03/2010; 21(9):1031-7. · 3.06 Impact Factor
