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Wei Zou,
Takashi Izawa,
Tingting Zhu,
Jean Chappel,
Karel Otero,
Susan J Monkley,
David R Critchley, Brian G Petrich,
Alexei Morozov,
Mark H Ginsberg,
Steven L Teitelbaum
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ABSTRACT: To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts, or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs M-CSF-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and RANK ligand, but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼5 fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function and their selective inhibition, in mature osteoclasts, retards pathological bone loss.
Molecular and cellular biology 12/2012; · 6.06 Impact Factor
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ABSTRACT: In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin-3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1-deficient neutrophils, whereas only arrest is defective in kindlin-3-deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation.
Blood 03/2012; 119(18):4275-82. · 9.90 Impact Factor
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ABSTRACT: The modulation of integrin affinity is central to platelet and leukocyte function. Two proteins, talin and kindlin, that interact with distinct regions of integrin cytoplasmic domains, have been shown to play essential roles in inducing the high affinity integrin conformation required for platelet and leukocyte adhesive interactions.Here we highlight some of the key studies that have described roles for talin and kindlin in integrin function and discuss several models that explain how talin and kindlins might work together to regulate integrin activation.
Genetic deletion of kindlin-3 in mice results in platelet and leukocyte adhesive dysfunction associated with profoundly impaired activation of multiple classes of integrins, a phenotype similar to that observed in talin-deficient platelets and leukocytes. Since this initial report three years ago, numerous studies have provided important clues to how kindlins activate integrins and, in some cases, the relationship between kindlins and talin in integrin activation.
Clearly, talin and kindlins are key regulators of integrin affinity. Future experiments that define precisely how these molecules work in concert should provide important insights into the terminal signaling events that activate integrins.
Current opinion in hematology 09/2011; 18(5):356-60. · 5.19 Impact Factor
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ABSTRACT: Neutrophil recruitment to sites of inflammation involves P-selectin-dependent rolling. qDF is a useful tool to visualize the topography of the neutrophil footprint as it interacts with the substrate. However, elucidating the role of specific proteins in addition to topography requires simultaneous visualization of two fluorochromes.
To validate DqDF, mouse neutrophils were labeled with the membrane dyes DiO and DiI and perfused into microchannels coated with P-selectin-Fc. Footprints of rolling neutrophils were recorded as two separate images, one for each fluorochrome. To assess the localization of the cytoskeletal protein paxillin, we applied DqDF to DiO-stained neutrophils of mice expressing an mCherry-paxillin fusion protein.
The footprint topographies obtained from DiO and DiI in the plasma membrane were identical. The z-coordinates of the microvilli tips obtained with the two fluorochromes in the footprint were also identical. Paxillin was found to be localized to some, but not all ridges in the neutrophil footprint.
Our data suggest that the spectral properties of the fluorochrome do not affect the results. DqDF will be useful for simultaneous visualization of two fluorochromes in the footprint of rolling cells.
Microcirculation (New York, N.Y.: 1994) 02/2011; 18(5):361-72. · 2.37 Impact Factor
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ABSTRACT: Talin functions both as a regulator of integrin affinity and as an important mechanical link between integrins and the cytoskeleton. Using genetic deletion of talin, we show for the first time that the capacity of talin to activate integrins is required for fibrin clot retraction by platelets. To further dissect which talin functions are required for this process, we tested clot retraction in platelets expressing a talin1(L325R) mutant that binds to integrins, but exhibits impaired integrin activation ascribable to disruption of the interaction between talin and the membrane-proximal region (MPR) in the β-integrin cytoplasmic domain. Talin-deficient and talin1(L325R) platelets were defective in retracting fibrin clots. However, the defect in clot retraction in talin1(L325R) platelets, but not talin-deficient platelets, was rescued by extrinsically activating integrins with manganese, thereby proving that integrin activation is required and showing that talin1(L325R) can form functional links to the actin cytoskeleton.
Blood 10/2010; 117(5):1719-22. · 9.90 Impact Factor
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ABSTRACT: Extracellular antagonists of alpha 4 integrin are an effective therapy for several autoimmune and inflammatory diseases; however, these agents that directly block ligand binding may exhibit mechanism-based toxicities. Inhibition of alpha 4 integrin signaling by mutations of alpha 4 that block paxillin binding inhibits inflammation while limiting mechanism-based toxicities. Here, we test a pharmacological approach by identifying small molecules that inhibit the alpha 4 integrin-paxillin interaction. By screening a large (approximately 40,000-compound) chemical library, we identified a noncytotoxic inhibitor of this interaction that impaired integrin alpha 4-mediated but not alpha L beta 2-mediated Jurkat T cell migration. The identified compound had no effect on alpha 4-mediated migration in cells bearing the alpha 4(Y991A) mutation that disrupts the alpha 4-paxillin interaction, establishing the specificity of its action. Administration of this compound to mice led to impaired recruitment of mononuclear leukocytes to a site of inflammation in vivo, whereas an isomer that does not inhibit the alpha 4-paxillin interaction had no effect on alpha 4-mediated cell migration, cell spreading, or recruitment of leukocytes to an inflammatory site. Thus, a small molecule inhibitor that interferes with alpha 4 integrin signaling reduces alpha 4-mediated T cell migration in vivo, thus providing proof of principle for inhibition of alpha 4 integrin signaling as a target for the pharmacological reduction of inflammation.
Journal of Biological Chemistry 03/2010; 285(13):9462-9. · 4.77 Impact Factor
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Brian G Petrich
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ABSTRACT: Integrins are heterodimeric adhesion receptors essential for metazoan life. In addition to mediating cell-extracellular matrix and cell-cell interactions, integrins are bona fide signalling receptors in that they transmit information in both directions across the plasma membrane. The affinity of integrins for extracellular ligands is regulated through a process termed integrin activation or "inside-out signalling". On the other hand, ligand binding to integrins can induce the recruitment and activation of a number of enzymes and adaptors such as pp125(FAK) and Src family kinases, to initiate "outside-in signalling". Intensive investigation into the mechanisms of integrin signalling has revealed many of the key players; amongst these, one of the most important is talin. Our understanding of how many of these molecules interact is now understood at the atomic level thanks to detailed structural studies. Indeed structural information and model cell systems have provided unique opportunities to dissect the molecular mechanisms of many aspects of integrin signalling. Recent studies have begun testing the biological significance of these mechanisms using in-vivo models, particular genetically modified mice. The generation and characterisation of in-vivo models to study integrin signalling has provided valuable information into the functional significance of integrin signalling in fundamental physiological processes as well as within the context of human disease. Here, I will review recent insights that have been gained into integrin signalling through the use of genetically modified mice focusing on integrin alphaIIbbeta3 (GPIIb-IIIa) and the regulation of its function in haemostasis and thrombosis.
Thrombosis and Haemostasis 07/2009; 101(6):1020-4. · 5.04 Impact Factor
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Yanfeng Wang,
Rustem I Litvinov,
Xinsheng Chen,
Tami L Bach,
Lurong Lian, Brian G Petrich,
Susan J Monkley,
Yasunori Kanaho,
David R Critchley,
Takehiko Sasaki,
Morris J Birnbaum,
John W Weisel,
John Hartwig,
Charles S Abrams
The Journal of clinical investigation 01/2009; · 15.39 Impact Factor
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ABSTRACT: alphaIIbbeta3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a "beta3(Delta760-762)" knockin mouse was generated that lacked the 3 C-terminal beta3 residues (arginine-glycine-threonine [RGT]) necessary for alphaIIbbeta3 interaction with c-Src, but retained beta3 residues necessary for talin-dependent fibrinogen binding. beta3(Delta760-762) mice were compared with wild-type beta3(+/+) littermates, beta3(+/-) heterozygotes, and knockin mice where beta3 RGT was replaced by beta1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas beta3(+/+), beta3(+/-) and beta3/beta1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, beta3(Delta760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including beta3 (Tyr(747)). Unlike control mice, beta3(Delta760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl(3). Some beta3(Delta760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to beta3(Delta760-762) platelets was normal in response to saturating concentrations of protease-activated receptor 4 or glycoprotein VI agonists, but responses to adenosine diphosphate were impaired. Thus, deletion of beta3 RGT disrupts c-Src-mediated alphaIIbbeta3 signaling and confers protection from arterial thrombosis. Consequently, targeting alphaIIbbeta3 signaling may represent a feasible antithrombotic strategy.
Blood 12/2008; 113(15):3585-92. · 9.90 Impact Factor
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ABSTRACT: Adhesion of platelets to blood vessel walls is a shear stress dependent process that promotes arrest of bleeding and is mediated by the interaction of receptors expressed on platelets with various extracellular matrix (ECM) proteins that may become exposed upon vascular injury. Studies of dynamic platelet adhesion to ECM-coated substrates in conventional flow chambers require substantial fluid volumes and are difficult to perform with blood samples from a single laboratory mouse. Here we report dynamic platelet adhesion assays in two new microfluidic devices made of PDMS. Small cross-sections of the flow chambers in the devices reduce the blood volume requirements to <100 microl per assay, making the assays compatible with samples of whole blood obtained from a single mouse. One device has an array of 8 flow chambers with shear stress varying by a factor of 1.93 between adjacent chambers, covering a 100-fold range from low venous to arterial. The other device allows simultaneous high-resolution fluorescence imaging of dynamic adhesion of platelets from two different blood samples. Adhesion of platelets in the devices to three common ECM substrate coatings was verified to conform with published results. The devices were subsequently used to study the roles of extracellular and intracellular domains of integrin alphaIIbbeta3, a platelet receptor that is a central mediator of platelet aggregation and thrombus formation. The study involved wild-type mice and two genetically modified mouse strains and showed that the absence of the integrin impaired adhesion at all shear stresses, whereas a mutation in its intracellular domain reduced the adhesion only at moderate and high stresses. Because of small sample volumes required, the devices could be employed in research with genetically-modified model organisms and for adhesion tests in clinical settings with blood from neonates.
Lab on a Chip 10/2008; 8(9):1486-95. · 5.67 Impact Factor
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Yanfeng Wang,
Rustem I Litvinov,
Xinsheng Chen,
Tami L Bach,
Lurong Lian, Brian G Petrich,
Susan J Monkley,
Yasunori Kanaho,
David R Critchley,
Takehiko Sasaki,
Morris J Birnbaum,
John W Weisel,
John Hartwig,
Charles S Abrams
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ABSTRACT: Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is an abundant phospholipid that contributes to second messenger formation and has also been shown to contribute to the regulation of cytoskeletal dynamics in all eukaryotic cells. Although the alpha, beta, and gamma isoforms of phosphatidylinositol-4-phosphate-5-kinase I (PIP5KI) all synthesize PIP2, mammalian cells usually contain more than one PIP5KI isoform. This raises the question of whether different isoforms of PIP5KI fulfill different functions. Given the speculated role of PIP(2) in platelet and megakaryocyte actin dynamics, we analyzed murine megakaryocytes lacking individual PIP5KI isoforms. PIP5KIgamma(-/-) megakaryocytes exhibited plasma membrane blebbing accompanied by a decreased association of the membrane with the cytoskeleton. This membrane defect was rescued by adding back wild-type PIP5KIgamma, but not by adding a catalytically inactive mutant or a splice variant lacking the talin-binding motif. Notably, both PIP5KIbeta- and PIP5KIgamma(-/-) cells had impaired PIP(2) synthesis. However, PIP5KIbeta-null cells lacked the membrane-cytoskeleton defect. Furthermore, overexpressing PIP5KIbeta in PIP5KIgamma(-/-) cells failed to revert this defect. Megakaryocytes lacking the PIP5KIgamma-binding partner, talin1, mimicked the membrane-cytoskeleton defect phenotype seen in PIP5KIgamma(-/-) cells. These findings demonstrate a unique role for PIP5KIgamma in the anchoring of the cell membrane to the cytoskeleton in megakaryocytes, probably through a pathway involving talin. These observations further demonstrate that individual PIP5KI isoforms fulfill distinct functions within cells.
Journal of Clinical Investigation 03/2008; 118(2):812-9. · 15.39 Impact Factor
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Brian G Petrich,
Patrizia Marchese,
Zaverio M Ruggeri,
Saskia Spiess,
Rachel A M Weichert,
Feng Ye,
Ralph Tiedt,
Radek C Skoda,
Susan J Monkley,
David R Critchley,
Mark H Ginsberg
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ABSTRACT: Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin alphaIIbbeta3-mediated platelet aggregation and beta1 integrin-mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet beta1 and beta3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian alpha2beta1 and alphaIIbbeta3 integrins in vivo.
Journal of Experimental Medicine 01/2008; 204(13):3103-11. · 13.85 Impact Factor
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ABSTRACT: In vitro studies indicate that binding of talin to the beta(3) integrin cytoplasmic domain (tail) results in integrin alpha(IIb)beta(3) (GPIIb-IIIa) activation. Here we tested the importance of talin binding for integrin activation in vivo and its biological significance by generating mice harboring point mutations in the beta(3) tail. We introduced a beta(3)(Y747A) substitution that disrupts the binding of talin, filamin, and other cytoplasmic proteins and a beta(3)(L746A) substitution that selectively disrupts interactions only with talin. Platelets from animals homozygous for each mutation showed impaired agonist-induced fibrinogen binding and platelet aggregation, providing proof that inside-out signals that activate alpha(IIb)beta(3) require binding of talin to the beta(3) tail. beta(3)(L746A) mice were resistant to both pulmonary thromboembolism and to ferric chloride-induced thrombosis of the carotid artery. Pathological bleeding, measured by the presence of fecal blood and development of anemia, occurred in 53% of beta(3)(Y747A) and virtually all beta(3)-null animals examined. Remarkably, less than 5% of beta(3)(L746A) animals exhibited this form of bleeding. These results establish that alpha(IIb)beta(3) activation in vivo is dependent on the interaction of talin with the beta(3) integrin cytoplasmic domain. Furthermore, they suggest that modulation of beta(3) integrin-talin interactions may provide an attractive target for antithrombotics and result in a reduced risk of pathological bleeding.
Journal of Clinical Investigation 09/2007; 117(8):2250-9. · 15.39 Impact Factor
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ABSTRACT: Decreases in the expression of connexin 43 and the integrity of gap junctions in cardiac muscle, induced by the constitutive activation of the c-Jun N-terminal kinase (JNK) signaling pathway, have been linked to conduction defects and sudden cardiac failure in mice [Petrich BG, Gong X , Lerner DL , Wang X , Brown JH , Saffitz JE , Wang Y. c-Jun N-terminal kinase activation mediates downregulation of connexin 43 in cardiomyocytes. Circ Res. 91 (2002) 640-647; B.G. Petrich, B.C. Eloff, D.L. Lerner, A. Kovacs, J.E. Saffitz, D.S. Rosenbaum, Y. Wang, Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J. Biol. Chem. 2004;279: 15330-15338]. We examined the membrane cytoskeletal protein, alphaII-spectrin, which associates with connexin 43, to learn if changes in its association with connexin 43 are linked to the instability of gap junctions. Several forms of alphaII-spectrin are expressed in the heart, including one, termed alphaII-SH3i, which contains a 20-amino-acid sequence next to the SH3 domain of repeat 10. In adult mouse heart, antibodies to all forms of alphaII-spectrin labeled the sarcolemma, transverse ("t-") tubules and intercalated disks of cardiomyocytes. In contrast, antibodies specific for alphaII-SH3i labeled only gap junctions and transverse tubules. In transgenic hearts, in which the JNK pathway was constitutively activated, alphaII-SH3i was lost specifically from gap junctions but not from t-tubules while other isoforms of alphaII-spectrin were retained at intercalated disks. Immunoprecipitations confirmed the decreased association of alphaII-SH3i with connexin 43 in transgenic hearts compared to controls. Furthermore, activation of JNK in neonatal myocytes blocked the formation of gap junctions by exogenously expressed Cx43-GFP fusion protein. Similarly, overexpression of the SH3i fragment in the context of repeats 9-11 of alphaII-spectrin specifically caused the accumulation of Cx43-GFP in the perinuclear region and inhibited its accumulation at gap junctions. These results support a critical role for the alphaII-SH3i isoform of spectrin in intracellular targeting of Cx43 to gap junctions and implicates alphaII-SH3i as a potential target for stress signaling pathways that modulate intercellular communication.
Journal of Molecular and Cellular Cardiology 04/2007; 42(3):572-81. · 5.17 Impact Factor
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ABSTRACT: The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died approximately 7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor beta signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.
Journal of Biological Chemistry 05/2004; 279(15):15330-8. · 4.77 Impact Factor
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ABSTRACT: Activation of stress-activated mitogen-activated protein kinases (SAPKs), mainly c-Jun N-terminal kinase (JNK) and p38, have long been associated with different forms of cardiac pathology across a wide spectrum of species. However, their specific roles in the development of heart failure are still unclear. Previous studies in neonatal myocytes in culture suggest a critical role for both JNK and p38 in hypertrophy and apoptosis. A far more complex picture has been provided by recent observations from both cellular and transgenic models that have not only challenged their role in hypertrophy and cell death but have also pointed out novel functions of SAPKs in different aspects of cardiac pathology, including contractile function, extracellular matrix remodeling, intercellular communication, and metabolic regulation.
Trends in Cardiovascular Medicine 03/2004; 14(2):50-5. · 2.49 Impact Factor
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ABSTRACT: Using a cre-loxP-mediated gene-switch approach, we achieved targeted JNK activation in adult hearts. A transgenic model is established carrying a floxed gene-switch construct that directs GFP marker gene expression in the absence of DNA recombination between two loxP sites. A tamoxifen-inducible Cre recombinase was introduced in the transgenic heart by breeding with previously established Mer-Cre-Mer transgenic mice. Upon tamoxifen administration in double transgenic adult animals, cre-loxP-mediated DNA recombination efficiently switches "off" the loxP-flanked GFP expression unit in cardiomyocytes and switches "on" the expression of the target gene, MKK7D, a constitutively activated upstream activator of c-Jun N-terminal kinases (JNK). Expression of MKK7D in adult hearts resulted in significant activation of JNK activities and causes progressive cardiomyopathy in transgenic animals. This unique animal model of cardiac-specific and temporally regulated JNK activation will provide a powerful tool to investigate the functional role of the JNK pathway in the development of heart failure. Our data also demonstrated that the inducible gene-switch approach reported here may also be applicable in other studies to achieve efficient, tissue-specific, and temporally regulated genetic manipulation in intact animals.
The FASEB Journal 05/2003; 17(6):749-51. · 5.71 Impact Factor
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ABSTRACT: Loss of gap junctions and impaired intercellular communication are characteristic features of pathological remodeling in heart failure as a result of stress or injury, yet the underlying regulatory mechanism has not been identified. Here, we report that in cultured myocytes, rapid loss of the gap junction protein connexin43 (Cx43) occurs in conjunction with the activation of c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, on stress stimulation. To investigate the specific role of JNK activation in the regulation of connexin in cardiomyocytes, an activated mutant of mitogen-activated protein kinase kinase 7 (mutant D), a JNK-specific upstream activator, was expressed in myocytes by adenovirus-mediated gene transfer. JNK activation in infected cardiomyocytes resulted in significant reduction of Cx43 expression at both mRNA and protein levels and impaired cell-cell communication. To evaluate the role of JNK in the regulation of Cx43 expression and gap junction structure in vivo, a Cre-LoxP-mediated gene-switch system was used to establish a transgenic animal model with targeted activation of JNK in ventricular myocardium. The transgenic hearts exhibited significant downregulation of Cx43 expression and loss of gap junctions in myocardium that may contribute to the cardiac dysfunction and premature death phenotype. Our report represents the first evidence, both in vitro and in vivo, implicating JNK as an important mediator of stress-induced Cx43 downregulation and impaired intercellular communication in the failing heart.
Circulation Research 11/2002; 91(7):640-7. · 9.49 Impact Factor
