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Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes.
Fenix AM, Neininger AC, Taneja N, Hyde K, Visetsouk MR, Garde RJ, Liu B, Nixon BR, Manalo AE, Becker JR, Crawley SW, Bader DM, Tyska MJ, Liu Q, Gutzman JH, Burnette DT
(2018) Elife 7:
MeSH Terms: Actin Cytoskeleton, Actins, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Microfilament Proteins, Microscopy, Confocal, Molecular Motor Proteins, Muscle Fibers, Skeletal, Myocytes, Cardiac, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, RNA Interference, Sarcomeres, Stress Fibers
Show Abstract · Added March 27, 2019
The sarcomere is the contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating actin and myosin filament assembly during sarcomere formation. Therefore, we developed an assay using human cardiomyocytes to monitor sarcomere assembly. We report a population of muscle stress fibers, similar to actin arcs in non-muscle cells, which are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from muscle stress fibers. This requires formins (e.g., FHOD3), non-muscle myosin IIA and non-muscle myosin IIB. Furthermore, we show short cardiac myosin II filaments grow to form ~1.5 μm long filaments that then 'stitch' together to form the stack of filaments at the core of the sarcomere (i.e., the A-band). A-band assembly is dependent on the proper organization of actin filaments and, as such, is also dependent on FHOD3 and myosin IIB. We use this experimental paradigm to present evidence for a unifying model of sarcomere assembly.
© 2018, Fenix et al.
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16 MeSH Terms
Inverted formin 2 regulates intracellular trafficking, placentation, and pregnancy outcome.
Lamm KYB, Johnson ML, Baker Phillips J, Muntifering MB, James JM, Jones HN, Redline RW, Rokas A, Muglia LJ
(2018) Elife 7:
MeSH Terms: Animals, Cell Differentiation, Cell Movement, Female, Mice, Mice, Knockout, Microfilament Proteins, Placentation, Pregnancy, Pregnancy Outcome, Trophoblasts
Show Abstract · Added March 21, 2018
Healthy pregnancy depends on proper placentation-including proliferation, differentiation, and invasion of trophoblast cells-which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of ( alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of in mice recapitulates maternal and fetal phenotypes of placental insufficiency. dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for in trophoblast invasion-a necessary process for placentation-representing a possible future target for improving placentation and fetal outcomes.
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11 MeSH Terms
Impact of cordon-bleu expression on actin cytoskeleton architecture and dynamics.
Grega-Larson NE, Crawley SW, Tyska MJ
(2016) Cytoskeleton (Hoboken) 73: 670-679
MeSH Terms: Actin Cytoskeleton, Animals, Cell Line, Tumor, Gene Expression Regulation, Mice, Microfilament Proteins, Microvilli, Proteins
Show Abstract · Added April 7, 2017
Cordon-bleu (COBL) is a multifunctional WASP-Homology 2 (WH2) domain-containing protein implicated in a wide variety of cellular functions ranging from dendritic arborization in neurons to the assembly of microvilli on the surface of transporting epithelial cells. In vitro biochemical studies suggest that COBL is capable of nucleating and severing actin filaments, among other activities. How the multiple activities of COBL observed in vitro contribute to its function in cells remains unclear. Here, we used live imaging to evaluate the impact of COBL expression on the actin cytoskeleton in cultured cells. We found that COBL induces the formation of dynamic linear actin structures throughout the cytosol. We also found that stabilizing these dynamic structures with the parallel actin-bundling protein espin slows down their turnover and enables the robust formation of self-supported protrusions on the dorsal cell surface. Super-resolution imaging revealed a global remodeling of the actin cytoskeleton in cells expressing these two factors. Taken together, these results provide insight as to how COBL contributes to the assembly of actin-based structures such as epithelial microvilli. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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8 MeSH Terms
Cortactin promotes exosome secretion by controlling branched actin dynamics.
Sinha S, Hoshino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, Tyska MJ, Weaver AM
(2016) J Cell Biol 214: 197-213
MeSH Terms: Actin-Related Protein 2-3 Complex, Actins, Biological Transport, Cell Line, Tumor, Cell Membrane, Cortactin, Exosomes, Humans, Microfilament Proteins, Models, Biological, Molecular Docking Simulation, Multivesicular Bodies, Phenotype, Protein Binding, Pseudopodia, RNA, Small Interfering, Tetraspanin 30, rab GTP-Binding Proteins
Show Abstract · Added April 7, 2017
Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites.
© 2016 Sinha et al.
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18 MeSH Terms
Loss of CENP-F results in distinct microtubule-related defects without chromosomal abnormalities.
Pfaltzgraff ER, Roth GM, Miller PM, Gintzig AG, Ohi R, Bader DM
(2016) Mol Biol Cell 27: 1990-9
MeSH Terms: Animals, Cell Cycle, Centromere, Chromosomal Proteins, Non-Histone, Chromosome Aberrations, Chromosome Segregation, Fibroblasts, Interphase, Kinetochores, Mice, Mice, Knockout, Microfilament Proteins, Microtubules, Mitosis, Protein Binding
Show Abstract · Added March 29, 2017
Microtubule (MT)-binding centromere protein F (CENP-F) was previously shown to play a role exclusively in chromosome segregation during cellular division. Many cell models of CENP-F depletion show a lag in the cell cycle and aneuploidy. Here, using our novel genetic deletion model, we show that CENP-F also regulates a broader range of cellular functions outside of cell division. We characterized CENP-F(+/+) and CENP-F(-/-) mouse embryonic fibroblasts (MEFs) and found drastic differences in multiple cellular functions during interphase, including cell migration, focal adhesion dynamics, and primary cilia formation. We discovered that CENP-F(-/-) MEFs have severely diminished MT dynamics, which underlies the phenotypes we describe. These data, combined with recent biochemical research demonstrating the strong binding of CENP-F to the MT network, support the conclusion that CENP-F is a powerful regulator of MT dynamics during interphase and affects heterogeneous cell functions.
© 2016 Pfaltzgraff et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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15 MeSH Terms
Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress.
Hines-Beard J, Bond WS, Backstrom JR, Rex TS
(2016) J Neuroinflammation 13: 39
MeSH Terms: Animals, Calcium-Binding Proteins, Cholera Toxin, Cytokines, Dependovirus, Disease Models, Animal, Erythropoietin, Evoked Potentials, Visual, Fluorescein Angiography, Gene Expression Regulation, Genetic Therapy, Glaucoma, Ki-67 Antigen, Mice, Mice, Inbred DBA, Microfilament Proteins, Microglia, Oxidative Stress, Photic Stimulation, Retina, Transduction, Genetic
Show Abstract · Added April 2, 2019
BACKGROUND - Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E.
METHODS - Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed.
RESULTS - Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
CONCLUSIONS - Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress.
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MeSH Terms
Extracellular rigidity sensing by talin isoform-specific mechanical linkages.
Austen K, Ringer P, Mehlich A, Chrostek-Grashoff A, Kluger C, Klingner C, Sabass B, Zent R, Rief M, Grashoff C
(2015) Nat Cell Biol 17: 1597-606
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Biosensing Techniques, Blotting, Western, Cell Adhesion, Cells, Cultured, Extracellular Matrix, Fibroblasts, Fluorescence Resonance Energy Transfer, Focal Adhesions, Luminescent Proteins, Mechanical Phenomena, Mice, Knockout, Mice, Transgenic, Microfilament Proteins, Microscopy, Confocal, Microscopy, Fluorescence, Optical Tweezers, Peptides, Protein Binding, Talin, Vinculin
Show Abstract · Added February 4, 2016
The ability of cells to adhere and sense differences in tissue stiffness is crucial for organ development and function. The central mechanisms by which adherent cells detect extracellular matrix compliance, however, are still unknown. Using two single-molecule-calibrated biosensors that allow the analysis of a previously inaccessible but physiologically highly relevant force regime in cells, we demonstrate that the integrin activator talin establishes mechanical linkages following cell adhesion, which are indispensable for cells to probe tissue stiffness. Talin linkages are exposed to a range of piconewton forces and bear, on average, 7-10 pN during cell adhesion depending on their association with F-actin and vinculin. Disruption of talin's mechanical engagement does not impair integrin activation and initial cell adhesion but prevents focal adhesion reinforcement and thus extracellular rigidity sensing. Intriguingly, talin mechanics are isoform specific so that expression of either talin-1 or talin-2 modulates extracellular rigidity sensing.
1 Communities
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23 MeSH Terms
Cordon bleu promotes the assembly of brush border microvilli.
Grega-Larson NE, Crawley SW, Erwin AL, Tyska MJ
(2015) Mol Biol Cell 26: 3803-15
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Cell Culture Techniques, HEK293 Cells, Humans, Mice, Microfilament Proteins, Microvilli, Protein Structure, Tertiary, Syndecan-2
Show Abstract · Added October 15, 2015
Microvilli are actin-based protrusions found on the surface of diverse cell types, where they amplify membrane area and mediate interactions with the external environment. In the intestinal tract, these protrusions play central roles in nutrient absorption and host defense and are therefore essential for maintaining homeostasis. However, the mechanisms controlling microvillar assembly remain poorly understood. Here we report that the multifunctional actin regulator cordon bleu (COBL) promotes the growth of brush border (BB) microvilli. COBL localizes to the base of BB microvilli via a mechanism that requires its proline-rich N-terminus. Knockdown and overexpression studies show that COBL is needed for BB assembly and sufficient to induce microvillar growth using a mechanism that requires functional WH2 domains. We also find that COBL acts downstream of the F-BAR protein syndapin-2, which drives COBL targeting to the apical domain. These results provide insight into a mechanism that regulates microvillar growth during epithelial differentiation and have significant implications for understanding the maintenance of intestinal homeostasis.
© 2015 Grega-Larson et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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11 MeSH Terms
miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach.
Sousa JF, Nam KT, Petersen CP, Lee HJ, Yang HK, Kim WH, Goldenring JR
(2016) Gut 65: 914-24
MeSH Terms: Adenocarcinoma, Biomarkers, Tumor, COUP Transcription Factor II, Gastric Mucosa, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 4, Humans, Metaplasia, MicroRNAs, Microfilament Proteins, Peptides, Stomach, Stomach Neoplasms, Transfection, Trefoil Factor-2, Trefoil Factor-3, Up-Regulation
Show Abstract · Added September 28, 2015
OBJECTIVE - Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both marked by gene expression alterations in comparison to normal stomach. Since miRNAs are important regulators of gene expression, we sought to investigate the role of miRNAs on the development of stomach metaplasias.
DESIGN - We performed miRNA profiling using a quantitative reverse transcription-PCR approach on laser capture microdissected human intestinal metaplasia and SPEM. Data integration of the miRNA profile with a previous mRNA profile from the same samples was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with selected miRNA mimics and inhibitors was used to evaluate their effects on the expression of putative targets and additional metaplasia markers.
RESULTS - We identified several genes as potential targets of miRNAs altered during metaplasia progression. We showed evidence that HNF4γ (upregulated in intestinal metaplasia) is targeted by miR-30 and that miR-194 targets a known co-regulator of HNF4 activity, NR2F2 (downregulated in intestinal metaplasia). Intestinal metaplasia markers such as VIL1, TFF2 and TFF3 were downregulated after overexpression of miR-30a in a HNF4γ-dependent manner. In addition, overexpression of HNF4γ was sufficient to induce the expression of VIL1 and this effect was potentiated by downregulation of NR2F2.
CONCLUSIONS - The interplay of the two transcription factors HNF4γ and NR2F2 and their coordinate regulation by miR-30 and miR-194, respectively, represent a miRNA to transcription factor network responsible for the expression of intestinal transcripts in stomach cell lineages during the development of intestinal metaplasia.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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17 MeSH Terms
The guanine nucleotide exchange factor (GEF) Asef2 promotes dendritic spine formation via Rac activation and spinophilin-dependent targeting.
Evans JC, Robinson CM, Shi M, Webb DJ
(2015) J Biol Chem 290: 10295-308
MeSH Terms: Actin Cytoskeleton, Amino Acid Sequence, Animals, Dendritic Spines, Embryo, Mammalian, Gene Expression Regulation, Developmental, Guanine Nucleotide Exchange Factors, Hippocampus, Microfilament Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Neurogenesis, Primary Cell Culture, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Rats, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Synapses
Show Abstract · Added February 5, 2016
Dendritic spines are actin-rich protrusions that establish excitatory synaptic contacts with surrounding neurons. Reorganization of the actin cytoskeleton is critical for the development and plasticity of dendritic spines, which is the basis for learning and memory. Rho family GTPases are emerging as important modulators of spines and synapses, predominantly through their ability to regulate actin dynamics. Much less is known, however, about the function of guanine nucleotide exchange factors (GEFs), which activate these GTPases, in spine and synapse development. In this study we show that the Rho family GEF Asef2 is found at synaptic sites, where it promotes dendritic spine and synapse formation. Knockdown of endogenous Asef2 with shRNAs impairs spine and synapse formation, whereas exogenous expression of Asef2 causes an increase in spine and synapse density. This effect of Asef2 on spines and synapses is abrogated by expression of GEF activity-deficient Asef2 mutants or by knockdown of Rac, suggesting that Asef2-Rac signaling mediates spine development. Because Asef2 interacts with the F-actin-binding protein spinophilin, which localizes to spines, we investigated the role of spinophilin in Asef2-promoted spine formation. Spinophilin recruits Asef2 to spines, and knockdown of spinophilin hinders spine and synapse formation in Asef2-expressing neurons. Furthermore, inhibition of N-methyl-d-aspartate receptor (NMDA) activity blocks spinophilin-mediated localization of Asef2 to spines. These results collectively point to spinophilin-Asef2-Rac signaling as a novel mechanism for the development of dendritic spines and synapses.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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19 MeSH Terms