38 results on '"Veevers, Jennifer"'
Search Results
2. Cell-Surface Marker Signature for Enrichment of Ventricular Cardiomyocytes Derived from Human Embryonic Stem Cells
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Veevers, Jennifer, Farah, Elie N, Corselli, Mirko, Witty, Alec D, Palomares, Karina, Vidal, Jason G, Emre, Nil, Carson, Christian T, Ouyang, Kunfu, Liu, Canzhao, van Vliet, Patrick, Zhu, Maggie, Hegarty, Jeffrey M, Deacon, Dekker C, Grinstein, Jonathan D, Dirschinger, Ralf J, Frazer, Kelly A, Adler, Eric D, Knowlton, Kirk U, C., Neil, Martin, Jody C, Chen, Ju, and Evans, Sylvia M
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Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research ,Heart Disease ,Biotechnology ,Regenerative Medicine ,Cardiovascular ,Stem Cell Research - Embryonic - Human ,Development of treatments and therapeutic interventions ,1.1 Normal biological development and functioning ,5.2 Cellular and gene therapies ,Underpinning research ,Antigens ,CD ,Cardiac Myosins ,Cell Differentiation ,Cell Line ,Cells ,Cultured ,Heart Ventricles ,Human Embryonic Stem Cells ,Humans ,Myocytes ,Cardiac ,Myosin Light Chains ,Trihexosylceramides ,cardiac differentiation ,cell-surface marker signature ,human embryonic stem cells ,ventricular cardiomyocytes ,Clinical Sciences ,Biochemistry and cell biology - Abstract
To facilitate understanding of human cardiomyocyte (CM) subtype specification, and the study of ventricular CM biology in particular, we developed a broadly applicable strategy for enrichment of ventricular cardiomyocytes (VCMs) derived from human embryonic stem cells (hESCs). A bacterial artificial chromosome transgenic H9 hESC line in which GFP expression was driven by the human ventricular-specific myosin light chain 2 (MYL2) promoter was generated, and screened to identify cell-surface markers specific for MYL2-GFP-expressing VCMs. A CD77+/CD200- cell-surface signature facilitated isolation of >97% cardiac troponin I-positive cells from H9 hESC differentiation cultures, with 65% expressing MYL2-GFP. This study provides a tool for VCM enrichment when using some, but not all, human pluripotent stem cell lines. Tools generated in this study can be utilized toward understanding CM subtype specification, and enriching for VCMs for therapeutic applications.
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- 2018
3. Generation and Analysis of Striated Muscle Selective LINC Complex Protein Mutant Mice
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Stroud, Matthew J, Fang, Xi, Veevers, Jennifer, and Chen, Ju
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Biochemistry and Cell Biology ,Biological Sciences ,Cardiovascular ,Rare Diseases ,Genetics ,Heart Disease ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,Musculoskeletal ,Alleles ,Amino Acid Substitution ,Animals ,Biomarkers ,CRISPR-Cas Systems ,Cytoskeleton ,Echocardiography ,Fluorescent Antibody Technique ,Gene Targeting ,Genotype ,Mice ,Mice ,Knockout ,Mice ,Transgenic ,Multiprotein Complexes ,Muscle ,Striated ,Mutation ,Nuclear Proteins ,LINC complex ,Nuclear envelope ,Knockout mouse ,Knock-in mouse ,Cre/loxP ,CRISPR/Cas9 ,Striated muscle ,Cardiac muscle ,Skeletal muscle ,Other Chemical Sciences ,Developmental Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
The linker of nucleoskeleton and cytoskeleton (LINC) complex mediates intracellular cross talk between the nucleus and the cytoplasm. In striated muscle, the LINC complex provides structural support to the myocyte nucleus and plays an essential role in regulating gene expression and mechanotransduction. A wide range of cardiac and skeletal myopathies have been linked to mutations in LINC complex proteins. Studies utilizing tissue-specific knockout and mutant mouse models have revealed important insights into the roles of the LINC complex in striated muscle. In this chapter, we describe several feasible approaches for generating striated muscle-specific gene knockout and mutant mouse models to study LINC complex protein function in cardiac and skeletal muscle. The experimental procedures used for phenotyping and analysis of LINC complex knockout mice are also described.
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- 2018
4. HSPB7 is indispensable for heart development by modulating actin filament assembly
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Wu, Tongbin, Mu, Yongxin, Bogomolovas, Julius, Fang, Xi, Veevers, Jennifer, Nowak, Roberta B, Pappas, Christopher T, Gregorio, Carol C, Evans, Sylvia M, Fowler, Velia M, and Chen, Ju
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Cardiovascular ,Heart Disease ,2.1 Biological and endogenous factors ,Aetiology ,Actin Cytoskeleton ,Animals ,Cardiomyopathies ,Cytoskeletal Proteins ,Female ,HSP27 Heat-Shock Proteins ,Heart ,Heart Defects ,Congenital ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Muscle Proteins ,Myocardium ,Myocytes ,Cardiac ,Organogenesis ,Sarcomeres ,Tropomodulin ,HSPB7 ,heart development ,sarcomere ,thin filament assembly ,actin polymerization - Abstract
Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within HSPB7 are associated with dilated cardiomyopathy and heart failure in human patients. However, the precise role of HSPB7 in the heart is still unclear. In this study, we generated global as well as cardiac-specific HSPB7 KO mouse models and found that loss of HSPB7 globally or specifically in cardiomyocytes resulted in embryonic lethality before embryonic day 12.5. Using biochemical and cell culture assays, we identified HSPB7 as an actin filament length regulator that repressed actin polymerization by binding to monomeric actin. Consistent with HSPB7's inhibitory effects on actin polymerization, HSPB7 KO mice had longer actin/thin filaments and developed abnormal actin filament bundles within sarcomeres that interconnected Z lines and were cross-linked by α-actinin. In addition, loss of HSPB7 resulted in up-regulation of Lmod2 expression and mislocalization of Tmod1. Furthermore, crossing HSPB7 null mice into an Lmod2 null background rescued the elongated thin filament phenotype of HSPB7 KOs, but double KO mice still exhibited formation of abnormal actin bundles and early embryonic lethality. These in vivo findings indicated that abnormal actin bundles, not elongated thin filament length, were the cause of embryonic lethality in HSPB7 KOs. Our findings showed an unsuspected and critical role for a specific small heat shock protein in directly modulating actin thin filament length in cardiac muscle by binding monomeric actin and limiting its availability for polymerization.
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- 2017
5. Barth Syndrome Cardiomyopathy: An Update
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Pang, Jing, primary, Bao, Yutong, additional, Mitchell-Silbaugh, Kalia, additional, Veevers, Jennifer, additional, and Fang, Xi, additional
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- 2022
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6. 128 Resident training in research fundamentals using an online, asynchronous course
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Blackard, Jason T, primary, Knapke, Jacqueline M., additional, Schuckman, Stephanie, additional, Veevers, Jennifer, additional, Hardie, William D., additional, Yadav, Ruchi, additional, Kahn, Alexa, additional, Lee, Patrick, additional, Terebelo, Sima, additional, and Ryan, Patrick H., additional
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- 2024
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7. Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
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Fang, Xi, Bogomolovas, Julius, Wu, Tongbin, Zhang, Wei, Liu, Canzhao, Veevers, Jennifer, Stroud, Matthew J, Zhang, Zhiyuan, Ma, Xiaolong, Mu, Yongxin, Lao, Dieu-Hung, Dalton, Nancy D, Gu, Yusu, Wang, Celine, Wang, Michael, Liang, Yan, Lange, Stephan, Ouyang, Kunfu, Peterson, Kirk L, Evans, Sylvia M, and Chen, Ju
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Biological Sciences ,Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Rare Diseases ,Genetics ,Cardiovascular ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Animals ,Apoptosis Regulatory Proteins ,Cardiomyopathies ,Coculture Techniques ,Echocardiography ,HSP70 Heat-Shock Proteins ,Heart Failure ,Heat-Shock Proteins ,Kaplan-Meier Estimate ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Molecular Chaperones ,Mutation ,Myocytes ,Cardiac ,Phenotype ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
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- 2017
8. Nesprin 1α2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle
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Stroud, Matthew J, Feng, Wei, Zhang, Jianlin, Veevers, Jennifer, Fang, Xi, Gerace, Larry, and Chen, Ju
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Biochemistry and Cell Biology ,Medical Physiology ,Biomedical and Clinical Sciences ,Biological Sciences ,1.1 Normal biological development and functioning ,Underpinning research ,Musculoskeletal ,Actins ,Animals ,Binding Sites ,Cell Nucleus ,Cytoskeletal Proteins ,Genotype ,Kinesins ,Mice ,Inbred C57BL ,Mice ,Knockout ,Muscle Fibers ,Skeletal ,Mutation ,Myofibrils ,Nerve Tissue Proteins ,Nuclear Proteins ,Phenotype ,Protein Binding ,Protein Interaction Domains and Motifs ,Signal Transduction ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
The position of the nucleus in a cell is controlled by interactions between the linker of nucleoskeleton and cytoskeleton (LINC) complex and the cytoskeleton. Defects in nuclear positioning and abnormal aggregation of nuclei occur in many muscle diseases and correlate with muscle dysfunction. Nesprin 1, which includes multiple isoforms, is an integral component of the LINC complex, critical for nuclear positioning and anchorage in skeletal muscle, and is thought to provide an essential link between nuclei and actin. However, previous studies have yet to identify which isoform is responsible. To elucidate this, we generated a series of nesprin 1 mutant mice. We showed that the actin-binding domains of nesprin 1 were dispensable, whereas nesprin 1α2, which lacks actin-binding domains, was crucial for postnatal viability, nuclear positioning, and skeletal muscle function. Furthermore, we revealed that kinesin 1 was displaced in fibers of nesprin 1α2-knockout mice, suggesting that this interaction may play an important role in positioning of myonuclei and functional skeletal muscle.
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- 2017
9. CRISPR/Cas9-mediated gene manipulation to create single-amino-acid-substituted and floxed mice with a cloning-free method.
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Ma, Xiaolong, Chen, Chao, Veevers, Jennifer, Zhou, XinMin, Ross, Robert S, Feng, Wei, and Chen, Ju
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Animals ,Mice ,Knockout ,Mice ,Mutant Strains ,Protein Kinases ,Cloning ,Molecular ,Amino Acid Substitution ,Base Sequence ,Genome ,Gene Knockout Techniques ,CRISPR-Cas Systems ,Cloning ,Molecular ,Mice ,Knockout ,Mutant Strains - Abstract
Clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology is a powerful tool to manipulate the genome with extraordinary simplicity and speed. To generate genetically modified animals, CRISPR/Cas9-mediated genome editing is typically accomplished by microinjection of a mixture of Cas9 DNA/mRNA and single-guide RNA (sgRNA) into zygotes. However, sgRNAs used for this approach require manipulation via molecular cloning as well as in vitro transcription. Beyond these complexities, most mutants obtained with this traditional approach are genetically mosaic, yielding several types of cells with different genetic mutations. Recently, a growing body of studies has utilized commercially available Cas9 protein together with sgRNA and a targeting construct to introduce desired mutations. Here, we report a cloning-free method to target the mouse genome by pronuclear injection of a commercial Cas9 protein:crRNA:tracrRNA:single-strand oligodeoxynucleotide (ssODN) complex into mouse zygotes. As illustration of this method, we report the successful generation of global gene-knockout, single-amino-acid-substituted, as well as floxed mice that can be used for conditional gene-targeting. These models were produced with high efficiency to generate non-mosaic mutant mice with a high germline transmission rate.
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- 2017
10. Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure
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Zhang, Zhiyuan, Mu, Yongxin, Veevers, Jennifer, Peter, Angela K, Manso, Ana Maria, Bradford, William H, Dalton, Nancy D, Peterson, Kirk L, Knowlton, Kirk U, Ross, Robert S, Zhou, Xinmin, and Chen, Ju
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Medical Physiology ,Biomedical and Clinical Sciences ,Genetics ,Cardiovascular ,Heart Disease ,1.1 Normal biological development and functioning ,Underpinning research ,Age Factors ,Animals ,Cardiomyopathies ,Cytoskeletal Proteins ,Disease Progression ,Down-Regulation ,Fibrosis ,Gene Expression Regulation ,Developmental ,Genetic Predisposition to Disease ,Gestational Age ,Heart Failure ,Hypertrophy ,Left Ventricular ,Integrin beta1 ,Mice ,Knockout ,Muscle Proteins ,Myocytes ,Cardiac ,Phenotype ,cardiomyopathies ,integrins ,mice ,knockout ,myocytes ,cardiac ,sarcolemma ,myocytes ,cardiac ,Biochemistry and Cell Biology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
BackgroundThe striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.Methods and resultsThe current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart.ConclusionsKindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.
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- 2016
11. Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival.
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Mu, Yongxin, Jing, Ran, Peter, Angela K, Lange, Stephan, Lin, Lizhu, Zhang, Jianlin, Ouyang, Kunfu, Fang, Xi, Veevers, Jennifer, Zhou, Xinmin, Evans, Sylvia M, Cheng, Hongqiang, and Chen, Ju
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Myocardium ,Animals ,Mice ,Knockout ,Mice ,Cardiomyopathies ,Microfilament Proteins ,Adaptor Proteins ,Signal Transducing ,Muscle Proteins ,Protein Isoforms ,Risk Factors ,Embryonic Development ,Muscle ,Striated ,LIM Domain Proteins ,Cypher ,Enigma homolog protein ,Z‐line ,embryonic lethality ,Z-line ,Cardiovascular ,Genetics ,Heart Disease ,1.1 Normal biological development and functioning ,Cardiorespiratory Medicine and Haematology - Abstract
BackgroundThe striated muscle Z-line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Cypher and its close homologue, Enigma homolog protein (ENH), are 2 Z-line proteins previously shown to be individually essential for maintenance of postnatal cardiac function and stability of the Z-line during muscle contraction, but dispensable for cardiac myofibrillogenesis and development.Methods and resultsThe current studies were designed to test whether Cypher and ENH play redundant roles during embryonic development. Here, we demonstrated that mice lacking both ENH and Cypher exhibited embryonic lethality and growth retardation. Lethality in double knockout embryos was associated with cardiac dilation and abnormal Z-line structure. In addition, when ENH was ablated in conjunction with selective ablation of either Cypher short isoforms (CypherS), or Cypher long isoforms (CypherL), only the latter resulted in embryonic lethality.ConclusionsCypher and ENH redundantly play an essential role in sustaining Z-line structure from the earliest stages of cardiac function, and are redundantly required to maintain normal embryonic heart function and embryonic viability.
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- 2015
12. Linker of Nucleoskeleton and Cytoskeleton Complex Proteins in Cardiac Structure, Function, and Disease
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Stroud, Matthew J, Banerjee, Indroneal, Veevers, Jennifer, and Chen, Ju
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Heart Disease ,Cardiovascular ,Animals ,Cytoskeleton ,Heart Diseases ,Humans ,Myocytes ,Cardiac ,Nuclear Matrix ,Plakins ,cardiomyopathies ,cell nucleus ,myocytes ,cardiac ,myocytes ,cardiac ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of proteins within the inner and the outer nuclear membranes, connects the nuclear lamina to the cytoskeleton. The importance of this complex has been highlighted by the discovery of mutations in genes encoding LINC complex proteins, which cause skeletal or cardiac myopathies. Herein, this review summarizes structure, function, and interactions of major components of the LINC complex, highlights how mutations in these proteins may lead to cardiac disease, and outlines future challenges in the field.
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- 2014
13. Loss of eEF1A2 (Eukaryotic Elongation Factor 1 A2) in Murine Myocardium Results in Dilated Cardiomyopathy
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Feng, Wei, Wang, Li, Veevers, Jennifer, Liu, Canzhao, Huang, Titania, and Chen, Ju
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- 2021
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14. Mesenchymal stromal cell migration is regulated by fibronectin through integrin-mediated activation of PDGFR-β
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Veevers, Jennifer and Kielty, Catherine
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612.1 ,Platelet-derived growth factor ,Mesenchymal stromal cells ,Extracellular matrix - Abstract
Human adult mesenchymal stem cells (MSCs) derived from bone marrow have the capacity to self-renew and to differentiate into a variety of cells and tissues. They can leave their niche to migrate to remote tissues where they play a critical role in angiogenesis, wound repair and tissue regeneration. A major goal in adult stem cell research is to define how MSC fate is controlled by the pericellular extracellular matrix (ECM) and soluble factors that largely constitute their tissue-specific niches. Defining crucial regulatory signals that control the fate and function of MSCs in vitro will contribute to the development of therapeutic strategies to improve tissue regeneration. The objective of this study was to investigate the molecular relationships between cell-ECM integrin receptors and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, which are crucial in modulating MSC expansion, recruitment, and differentiation towards a number of different cell lineages. This study reports that ECM-directed cross-talk between PDGFR-β and alpha5β1 integrin controls the migration of MSCs. Cell adhesion to fibronectin induced integrin alpha5β1-dependent phosphorylation of PDGFR-β in the absence of growth factor stimulation. Phosphorylated PDGFR-β co-immunoprecipitated with integrin alpha5 and co-localised with alpha5β1 in a transient tidemark of focal adhesions. Adhesion to fibronectin also strongly potentiated platelet-derived growth factor (PDGF)-BB-stimulated PDGFR-β phosphorylation, in an alpha5β1-dependent manner. PDGFR-β-activated phosphatidylinositol 3 ́-kinase (PI3-kinase) and Akt activity, actin reorganisation and cell migration were all regulated by fibronectin engagement of alpha5β1 integrin. This synergistic relationship between integrin alpha5β1 and PDGFR-β is a fundamental determinant of mesenchymal cell migration. Thus, fibronectin-rich matrices can prime PDGFR-β to recruit mesenchymal cells at sites of tissue remodelling.
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- 2010
15. Environmental factors, epigenetics, and developmental origin of reproductive disorders
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Ho, Shuk-Mei, Cheong, Ana, Adgent, Margaret A., Veevers, Jennifer, Suen, Alisa A., Tam, Neville N.C., Leung, Yuet-Kin, Jefferson, Wendy N., and Williams, Carmen J.
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- 2017
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16. 123 Introducing trainees to research using an online, asynchronous course
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Blackard, Jason T., primary, Knapke, Jacqueline M., additional, Schuckman, Stephanie, additional, Veevers, Jennifer, additional, Hardie, William D., additional, and Ryan, Patrick H., additional
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- 2023
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17. 99 Grant Writing Program to Enhance Junior Faculty Research Funding Success
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Veevers, Jennifer, primary, Ryan, Patrick H., additional, Knapke, Jacqueline M., additional, Blackard, Jason T., additional, Schuckman, Stephanie, additional, Kissela, Brett M., additional, and Cushion, Melanie T., additional
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- 2023
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18. Generation and Analysis of Striated Muscle Selective LINC Complex Protein Mutant Mice
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Stroud, Matthew J., primary, Fang, Xi, additional, Veevers, Jennifer, additional, and Chen, Ju, additional
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- 2018
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19. Introducing trainees to research using an online, asynchronous course
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Blackard, Jason T., primary, Knapke, Jacqueline M., additional, Schuckman, Stephanie, additional, Veevers, Jennifer, additional, Hardie, William D., additional, and Ryan, Patrick H., additional
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- 2023
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20. Luma is not essential for murine cardiac development and function
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Stroud, Matthew J, Fang, Xi, Zhang, Jianlin, Guimarães-Camboa, Nuno, Veevers, Jennifer, Dalton, Nancy D, Gu, Yusu, Bradford, William H, Peterson, Kirk L, Evans, Sylvia M, Gerace, Larry, and Chen, Ju
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- 2018
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21. Research 101: An online course introducing medical students to research
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Blackard, Jason T., primary, Knapke, Jacqueline M., additional, Ryan, Patrick H., additional, Schuckman, Stephanie, additional, Veevers, Jennifer, additional, Hardie, William D., additional, and Heubi, James E., additional
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- 2022
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22. Loss of eukaryotic elongation factor 1 A2 (eEF1A2) in murine myocardium results in dilated cardiomyopathy
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Feng, Wei, Wang, Li, Veevers, Jennifer, Liu, Canzhao, Huang, Titania, and Chen, Ju
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Cardiomyopathy, Dilated ,Heart Failure ,Peptide Elongation Factor 1 ,Myocardium ,Animals ,Mice, Transgenic ,Article - Published
- 2021
23. Barth Syndrome Cardiomyopathy: An Update.
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Pang, Jing, Bao, Yutong, Mitchell-Silbaugh, Kalia, Veevers, Jennifer, and Fang, Xi
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CARDIOMYOPATHIES ,MITOCHONDRIAL pathology ,ACYLTRANSFERASES ,THERAPEUTICS ,SYNDROMES ,KNOCKOUT mice - Abstract
Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Brain manganese and the balance between essential roles and neurotoxicity
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Balachandran, Rekha C., primary, Mukhopadhyay, Somshuvra, additional, McBride, Danielle, additional, Veevers, Jennifer, additional, Harrison, Fiona E., additional, Aschner, Michael, additional, Haynes, Erin N., additional, and Bowman, Aaron B., additional
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- 2020
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25. Kindlin-2 Is Essential for Preserving Integrity of the Developing Heart and Preventing Ventricular Rupture
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Zhang, Zhiyuan, primary, Mu, Yongxin, additional, Zhang, Jianlin, additional, Zhou, Yangzhao, additional, Cattaneo, Paola, additional, Veevers, Jennifer, additional, Peter, Angela K., additional, Manso, Ana Maria, additional, Knowlton, Kirk U., additional, Zhou, Xinmin, additional, Evans, Sylvia M., additional, Ross, Robert S., additional, and Chen, Ju, additional
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- 2019
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26. P209L mutation in Bag3 does not cause cardiomyopathy in mice
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Fang, Xi, primary, Bogomolovas, Julius, additional, Zhou, Paul Shichao, additional, Mu, Yongxin, additional, Ma, Xiaolong, additional, Chen, Zee, additional, Zhang, Lunfeng, additional, Zhu, Mason, additional, Veevers, Jennifer, additional, Ouyang, Kunfu, additional, and Chen, Ju, additional
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- 2019
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27. Luma is not essential for murine cardiac development and function
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Stroud, Matthew J, primary, Fang, Xi, additional, Zhang, Jianlin, additional, Guimarães-Camboa, Nuno, additional, Veevers, Jennifer, additional, Dalton, Nancy D, additional, Gu, Yusu, additional, Bradford, William H, additional, Peterson, Kirk L, additional, Evans, Sylvia M, additional, Gerace, Larry, additional, and Chen, Ju, additional
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- 2017
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28. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk
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Leung, Yuet-Kin, primary, Govindarajah, Vinothini, additional, Cheong, Ana, additional, Veevers, Jennifer, additional, Song, Dan, additional, Gear, Robin, additional, Zhu, Xuegong, additional, Ying, Jun, additional, Kendler, Ady, additional, Medvedovic, Mario, additional, Belcher, Scott, additional, and Ho, Shuk-Mei, additional
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- 2017
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29. P209L mutation in Bag3 does not cause cardiomyopathy in mice.
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Xi Fang, Bogomolovas, Julius, Shichao Zhou, Paul, Yongxin Mu, Xiaolong Ma, Zee Chen, Lunfeng Zhang, Mason Zhu, Veevers, Jennifer, Kunfu Ouyang, and Ju Chen
- Abstract
Bcl-2-associated athanogene 3 (BAG3) is a cochaperone protein and a central player of the cellular protein quality control system. BAG3 is prominently expressed in the heart and plays an essential role in cardiac protein homeostasis by interacting with chaperone heat shock proteins (HSPs) in large, functionally distinct multichaperone complexes. The BAG3 mutation of proline 209 to leucine (P209L), which resides in a critical region that mediates the direct interaction between BAG3 and small HSPs (sHSPs), is associated with cardiomyopathy in humans. However, the mechanism by which the BAG3 P209L missense mutation leads to cardiomyopathy remains unknown. To determine the molecular basis underlying the cardiomyopathy caused by the BAG3 P209L mutation, we generated a knockin (KI) mouse model in which the endogenous Bag3 gene was replaced with mutant Bag3 containing the P215L mutation, which is equivalent to the human P209L mutation. We performed physiological, histological, and biochemical analyses of Bag3 P209L KI mice to determine the functional, morphological, and molecular consequences of the P209L mutation. We found that Bag3 P209L KI mice exhibited normal cardiac function and morphology up to 16 mo of age. Western blot analysis further revealed that levels of sHSPs, stress-inducible HSPs, ubiquitinated proteins, and autophagy were unaffected in P209L mutant mouse hearts. In conclusion, the P209L mutation in Bag3 does not cause cardiomyopathy in mice up to 16 mo of age under baseline conditions. NEW & NOTEWORTHY Bcl-2-associated athanogene 3 (BAG3) P209L mutation is associated with human cardiomyopathy. A recent study reported that transgenic mice overexpressing human BAG3 P209L in cardiomyocytes have cardiac dysfunction. In contrast, our P209L mice that express mutant BAG3 at the same level as that of wild-type mice displayed no overt phenotype. Our results suggest that human cardiomyopathy may result from species-specific requirements for the conserved motif that is disrupted by P209L mutation or from genetic background-dependent effects. [ABSTRACT FROM AUTHOR]
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- 2019
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30. Luma is not essential formurine cardiac development and function.
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Stroud, Matthew J., Xi Fang, Jianlin Zhang, Nuno Guimarães-Camboa, Veevers, Jennifer, Dalton, Nancy D., Yusu Gu, Bradford, William H., Peterson, Kirk L., Evans, Sylvia M., Gerace, Larry, and Ju Chen
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MEMBRANE proteins ,PROTEIN expression ,CYTOSKELETON ,CARDIOMYOPATHIES ,GENETIC mutation ,SERINE ,HEART cells - Abstract
Aims: Luma is a recently discovered, evolutionarily conserved protein expressed in mammalian heart, which is associated with the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex. The LINC complex structurally integrates the nucleus and the cytoplasm and plays a critical role in mechanotransduction across the nuclear envelope. Mutations in several LINC components in both humans and mice result in various cardiomyopathies, implying they play essential, non-redundant roles. A single amino acid substitution of serine 358 to leucine (S358L) in Luma is the unequivocal cause of a distinct form of arrhythmogenic cardiomyopathy. However, the role of Luma in heart has remained obscure. In addition, it also remains to be determined how the S358L mutation in Luma leads to cardiomyopathy. Methods And Results: To determine the role of Luma in the heart, we first determined the expression pattern of Luma in mouse heart. Luma was sporadically expressed in cardiomyocytes throughout the heart, but was highly and uniformly expressed in cardiac fibroblasts and vascular smooth muscle cells. We also generated germline null Luma mice and discovered that germline null mutants were viable and exhibited normal cardiac function. Luma null mice also responded normally to pressure overload induced by transverse aortic constriction. In addition, localization and expression of other LINC complex components in both cardiac myocytes and fibroblasts was unaffected by global loss of Luma. Furthermore, we also generated and characterized Luma S358L knock-in mice, which displayed normal cardiac function and morphology. Conclusion: Our data suggest that Luma is dispensable for murine cardiac development and function and that the Luma S358L mutation alone may not cause cardiomyopathy in mice. [ABSTRACT FROM AUTHOR]
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- 2018
- Full Text
- View/download PDF
31. HSPB7 is indispensable for heart development by modulating actin filament assembly.
- Author
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Tongbin Wu, Yongxin Mu, Bogomolovas, Julius, Xi Fang, Veevers, Jennifer, Nowak, Roberta B., Pappas, Christopher T., Gregorio, Carol C., Evans, Sylvia M., Fowler, Velia M., and Ju Chen
- Subjects
HEAT shock proteins ,ACTIN ,GENETIC mutation ,CARDIOMYOPATHIES ,CELL culture ,POLYMERIZATION - Abstract
Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within HSPB7 are associated with dilated cardiomyopathy and heart failure in human patients. However, the precise role of HSPB7 in the heart is still unclear. In this study, we generated global as well as cardiac-specific HSPB7 KO mouse models and found that loss of HSPB7 globally or specifically in cardiomyocytes resulted in embryonic lethality before embryonic day 12.5. Using biochemical and cell culture assays, we identified HSPB7 as an actin filament length regulator that repressed actin polymerization by binding to monomeric actin. Consistent with HSPB7's inhibitory effects on actin polymerization, HSPB7 KO mice had longer actin/thin filaments and developed abnormal actin filament bundles within sarcomeres that interconnected Z lines and were cross-linked by α-actinin. In addition, loss of HSPB7 resulted in up-regulation of Lmod2 expression and mislocalization of Tmod1. Furthermore, crossing HSPB7 null mice into an Lmod2 null background rescued the elongated thin filament phenotype of HSPB7 KOs, but double KO mice still exhibited formation of abnormal actin bundles and early embryonic lethality. These in vivo findings indicated that abnormal actin bundles, not elongated thin filament length, were the cause of embryonic lethality in HSPB7 KOs. Our findings showed an unsuspected and critical role for a specific small heat shock protein in directly modulating actin thin filament length in cardiac muscle by binding monomeric actin and limiting its availability for polymerization. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
32. Lmo7 is dispensable for skeletal muscle and cardiac function
- Author
-
Lao, Dieu Hung, primary, Esparza, Mary C., additional, Bremner, Shannon N., additional, Banerjee, Indroneal, additional, Zhang, Jianlin, additional, Veevers, Jennifer, additional, Bradford, William H., additional, Gu, Yusu, additional, Dalton, Nancy D., additional, Knowlton, Kirk U., additional, Peterson, Kirk L., additional, Lieber, Richard L., additional, and Chen, Ju, additional
- Published
- 2015
- Full Text
- View/download PDF
33. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk.
- Author
-
Yuet-Kin Leung, Govindarajah, Vinothini, Cheong, Ana, Veevers, Jennifer, Dan Song, Gear, Robin, Xuegong Zhu, Jun Ying, Kendler, Ady, Medvedovic, Mario, Belcher, Scott, and Shuk-Mei Ho
- Subjects
BISPHENOL A ,MOUSE mammary tumor virus ,DNA methylation ,EPIGENETICS ,MORPHOLOGY - Abstract
In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogeninduced mammary cancer risk in offspring, and its dose-response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a nonmonotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
34. Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure.
- Author
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Zhiyuan Zhang, Yongxin Mu, Veevers, Jennifer, Peter, Angela K., Manso, Ana Maria, Bradford, William H., Dalton, Nancy D., Peterson, Kirk L., Knowlton, Kirk U., Ross, Robert S., Xinmin Zhou, and Ju Chen
- Abstract
Background-The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined. Methods and Results-The current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart. Conclusions-Kindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
35. Lmo7 is dispensable for skeletal muscle and cardiac function.
- Author
-
Dieu Hung Lao, Esparza, Mary C., Bremner, Shannon N., Banerjee, Indroneal, Jianlin Zhang, Veevers, Jennifer, Bradford, William H., Yusu Gu, Dalton, Nancy D., Knowlton, Kirk U., Peterson, Kirk L., Lieber, Richard L., and Ju Chen
- Subjects
MUSCULAR dystrophy ,SKELETAL muscle ,MYOCARDIUM ,GENETIC mutation ,THERAPEUTIC use of proteins ,PATHOLOGICAL physiology ,PATIENTS - Abstract
Emery-Dreifuss muscular dystrophy (EDMD) is a degenerative disease primarily affecting skeletal muscles in early childhood as well as cardiac muscle at later stages. EDMD is caused by a number of mutations in genes encoding proteins associated with the nuclear envelope (e.g., Emerin, Lamin A/C, and Nesprin). Recently, a novel protein, Lim-domain only 7 (lmo7) has been reported to play a role in the molecular pathogenesis of EDMD. Prior in vitro and in vivo studies suggested the intriguing possibility that Lmo7 plays a role in skeletal or cardiac muscle pathophysiology. To further understand the in vivo role of Lmo7 in striated muscles, we generated a novel Lmo7-null (lmo7
-/- ) mouse line. Using this mouse line, we examined skeletal and cardiac muscle physiology, as well as the role of Lmo7 in a model of muscular dystrophy and regeneration using the dystrophin-deficient mdx mouse model. Our results demonstrated that lmo7-/- mice had no abnormalities in skeletal muscle morphology, physiological function, or regeneration. Cardiac function was also unaffected. Moreover, we found that ablation of lmo7 in mdx mice had no effect on the observed myopathy and muscular regeneration exhibited by mdx mice. Molecular analyses also showed no changes in dystrophin complex factors, MAPK pathway components, and Emerin levels in lmo7 knockout mice. Taken together, we conclude that Lmo7 is dispensable for skeletal muscle and cardiac physiology and pathophysiology. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
36. Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy.
- Author
-
Xi Fang, Bogomolovas, Julius, Tongbin Wu, Wei Zhang, Canzhao Liu, Veevers, Jennifer, Stroud, Matthew J., Zhiyuan Zhang, Xiaolong Ma, Yongxin Mu, Dieu-Hung Lao, Dalton, Nancy D., Yusu Gu, Wang, Celine, Wang, Michael, Yan Liang, Lange, Stephan, Kunfu Ouyang, Peterson, Kirk L., and Evans, Sylvia M.
- Subjects
- *
CARDIOMYOPATHIES , *MOLECULAR chaperones , *HEART cells , *HEART failure , *PHENOTYPES , *HEAT shock proteins - Abstract
Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
37. P209L mutation in Bag3 does not cause cardiomyopathy in mice.
- Author
-
Fang X, Bogomolovas J, Zhou PS, Mu Y, Ma X, Chen Z, Zhang L, Zhu M, Veevers J, Ouyang K, and Chen J
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Apoptosis Regulatory Proteins metabolism, Autophagy, Female, Heat-Shock Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Mutation, Missense, Myocytes, Cardiac metabolism, Myocytes, Cardiac physiology, Protein Binding, Species Specificity, Ubiquitination, Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Cardiomyopathies genetics
- Abstract
Bcl-2-associated athanogene 3 (BAG3) is a cochaperone protein and a central player of the cellular protein quality control system. BAG3 is prominently expressed in the heart and plays an essential role in cardiac protein homeostasis by interacting with chaperone heat shock proteins (HSPs) in large, functionally distinct multichaperone complexes. The BAG3 mutation of proline 209 to leucine (P209L), which resides in a critical region that mediates the direct interaction between BAG3 and small HSPs (sHSPs), is associated with cardiomyopathy in humans. However, the mechanism by which the BAG3 P209L missense mutation leads to cardiomyopathy remains unknown. To determine the molecular basis underlying the cardiomyopathy caused by the BAG3 P209L mutation, we generated a knockin (KI) mouse model in which the endogenous Bag3 gene was replaced with mutant Bag3 containing the P215L mutation, which is equivalent to the human P209L mutation. We performed physiological, histological, and biochemical analyses of Bag3 P209L KI mice to determine the functional, morphological, and molecular consequences of the P209L mutation. We found that Bag3 P209L KI mice exhibited normal cardiac function and morphology up to 16 mo of age. Western blot analysis further revealed that levels of sHSPs, stress-inducible HSPs, ubiquitinated proteins, and autophagy were unaffected in P209L mutant mouse hearts. In conclusion, the P209L mutation in Bag3 does not cause cardiomyopathy in mice up to 16 mo of age under baseline conditions. NEW & NOTEWORTHY Bcl-2-associated athanogene 3 (BAG3) P209L mutation is associated with human cardiomyopathy. A recent study reported that transgenic mice overexpressing human BAG3 P209L in cardiomyocytes have cardiac dysfunction. In contrast, our P209L mice that express mutant BAG3 at the same level as that of wild-type mice displayed no overt phenotype. Our results suggest that human cardiomyopathy may result from species-specific requirements for the conserved motif that is disrupted by P209L mutation or from genetic background-dependent effects.
- Published
- 2019
- Full Text
- View/download PDF
38. Lmo7 is dispensable for skeletal muscle and cardiac function.
- Author
-
Lao DH, Esparza MC, Bremner SN, Banerjee I, Zhang J, Veevers J, Bradford WH, Gu Y, Dalton ND, Knowlton KU, Peterson KL, Lieber RL, and Chen J
- Subjects
- Animals, Gene Expression genetics, LIM Domain Proteins metabolism, MAP Kinase Signaling System genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscular Dystrophy, Emery-Dreifuss genetics, Transcription Factors metabolism, Heart physiology, LIM Domain Proteins genetics, Muscle, Skeletal physiology, Muscular Dystrophy, Emery-Dreifuss pathology, Myocardium metabolism, Transcription Factors genetics
- Abstract
Emery-Dreifuss muscular dystrophy (EDMD) is a degenerative disease primarily affecting skeletal muscles in early childhood as well as cardiac muscle at later stages. EDMD is caused by a number of mutations in genes encoding proteins associated with the nuclear envelope (e.g., Emerin, Lamin A/C, and Nesprin). Recently, a novel protein, Lim-domain only 7 (lmo7) has been reported to play a role in the molecular pathogenesis of EDMD. Prior in vitro and in vivo studies suggested the intriguing possibility that Lmo7 plays a role in skeletal or cardiac muscle pathophysiology. To further understand the in vivo role of Lmo7 in striated muscles, we generated a novel Lmo7-null (lmo7(-/-)) mouse line. Using this mouse line, we examined skeletal and cardiac muscle physiology, as well as the role of Lmo7 in a model of muscular dystrophy and regeneration using the dystrophin-deficient mdx mouse model. Our results demonstrated that lmo7(-/-) mice had no abnormalities in skeletal muscle morphology, physiological function, or regeneration. Cardiac function was also unaffected. Moreover, we found that ablation of lmo7 in mdx mice had no effect on the observed myopathy and muscular regeneration exhibited by mdx mice. Molecular analyses also showed no changes in dystrophin complex factors, MAPK pathway components, and Emerin levels in lmo7 knockout mice. Taken together, we conclude that Lmo7 is dispensable for skeletal muscle and cardiac physiology and pathophysiology., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
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