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Alpadi, Kannan (1)
Baudier, Jacques (1)
Braskie, Meredith N. (1)
Cane, Stuart (1)
Chadwick, Richard S. (1)
Corleto, Jose A. (1)
Fath, Thomas (1)
Ferrier, Andrew (1)
Fridman, Vladimir (1)
Frolenkov, Gregory I. (1)
Gavara, Nuria (1)
Gay, Olivia (1)
Gerson-Gurwitz, Adina (1)
Gheber, Larisa (1)
Gilquin, Benoît (1)
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Guven, Kim (1)
Henderson, Beric R. (1)
Jahanshad, Neda (1)
Johnson, Michael A. (1)
Kelley, Matthew W. (1)
Kothary, Rashmi (1)
Kulkarni, Aditya (1)
Lyle, Karen S. (1)
Maresca, Thomas J. (1)
Martin, Nicholas G. (1)
McGilvray, Philip T. (1)
McMahon, Katie L. (1)
Namjoshi, Sarita (1)
Peters, Christopher (1)
Petralia, Ronald S. (1)
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Ryan, Scott D. (1)
Schmidt, Christoph F. (1)
Stepanyan, Ruben (1)
Szarama, Katherine B. (1)
Thiede, Christina (1)
Thompson, Paul M. (1)
Toga, Arthur W. (1)
Wittmann, Torsten (1)
Wright, Margaret J. (1)
de Zubicaray, Greig I. (1)
Year of Publication
Insights from an erroneous kinetochore-microtubule attachment state
McGilvray, Philip T.
Maresca, Thomas J.
Faithful distribution of the genome requires that sister kinetochores, which assemble on each chromatid during cell division, interact with dynamic microtubules from opposite spindle poles in a configuration called chromosome biorientation. Biorientation produces tension that increases the affinity of kinetochores for microtubules via ill-defined mechanisms. Non-bioriented kinetochore-microtubule (kt-MT) interactions are prevalent but short-lived due to an error correction pathway that reduces the affinity of kinetochores for microtubules. Interestingly, incorrect kt-MT interactions can be stabilized by experimentally applying force to misoriented chromosomes. Here, a live-cell force assay is utilized to characterize the molecular composition of a common type of improper kt-MT attachment. Our force-related studies are also discussed in the context of current models for tension-dependent stabilization of kt-MT interactions.
cell division; kinetochore; microtubule; syntelic attachment; error correction; spindle assembly checkpoint; aurora B kinase; Mad1; BubR1
Fibroblast growth factor receptor 3 regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti
Szarama, Katherine B.
Petralia, Ronald S.
Frolenkov, Gregory I.
Kelley, Matthew W.
Chadwick, Richard S.
Fibroblast Growth Factor (Fgf) signaling is involved in the exquisite cellular patterning of the developing cochlea, and is necessary for proper hearing function. Our previous data indicate that Fgf signaling disrupts actin, which impacts the surface stiffness of sensory outer hair cells (OHCs) and non-sensory supporting pillar cells (PCs) in the organ of Corti. Here, we used Atomic Force Microscopy (AFM) to measure the impact of loss of function of Fgf-receptor 3, on cytoskeletal formation and cell surface mechanical properties. We find a 50% decrease in both OHC and PC surface stiffness, and a substantial disruption in microtubule formation in PCs. Moreover, we find no change in OHC electromotility of Fgfr3-deficient mice. To further understand the regulation by Fgf-signaling on microtubule formation, we treated wild-type cochlear explants with Fgf-receptor agonist Fgf2, or antagonist SU5402, and find that both treatments lead to a significant reduction in β-Tubulin isotypes I&II. To identify downstream transcriptional targets of Fgf-signaling, we used QPCR arrays to probe 84 cytoskeletal regulators. Of the 5 genes significantly upregulated following treatment, Clasp2, Mapre2 and Mark2 impact microtubule formation. We conclude that microtubule formation is a major downstream effector of Fgf-receptor 3, and suggest this pathway impacts the formation of fluid spaces in the organ of Corti.
Fibroblast growth factor; Young’s modulus; hair cell; pillar cell
Microtubule dynamics regulation contributes to endothelial morphogenesis
Lyle, Karen S.
Corleto, Jose A.
Because little is known how microtubules contribute to cell migration in a physiological three-dimensional environment, we analyzed microtubule function and dynamics during in vitro angiogenesis in which endothelial cells form networks on a reconstituted basement membrane. Endothelial network formation resulted from distinct cell behaviors: matrix reorganization by myosin-mediated contractile forces, and active cell migration along reorganized, bundled matrix fibers. Inhibition of microtubule dynamics inhibited persistent cell migration, but not matrix reorganization. In addition, microtubule polymerization dynamics and CLASP2-binding to microtubules were spatially regulated to promote microtubule growth into endothelial cell protrusions along matrix tension tracks. We propose that microtubules counter-act contractile forces of the cortical actin cytoskeleton and are required to stabilize endothelial cell protrusions in a soft three-dimensional environment.
CLASP2; blebbistatin; cell migration; cytoskeleton; endothelial cells; in vitro angiogenesis; microtubule dynamics; nocodazole
How a common variant in the growth factor receptor gene, NTRK1, affects white matter
Braskie, Meredith N.
Toga, Arthur W.
McMahon, Katie L.
de Zubicaray, Greig I.
Martin, Nicholas G.
Wright, Margaret J.
Thompson, Paul M.
Growth factors and their receptors are important for cellular migration as well as axonal guidance and myelination in the brain. They also play a key role in programmed cell death, and are implicated in a number of mental illnesses. Recently, we reported that healthy young adults who carry the T allele variant in the growth factor gene, NTRK1 (at location rs6336), had lower white matter integrity than non-carriers on diffusion images of the brain. Diffusion tensor imaging (DTI) revealed how this single nucleotide polymorphism affects white matter microstructure in human populations; DTI is also used to identify characteristic features of brain connectivity in typically developing children and in patients. Newly discovered links between neuroimaging measures and growth factors whose molecular neuroscience is well known offer an important step in understanding mechanisms that contribute to brain connectivity. Altered fiber connectivity may mediate the relationship between some genetic risk factors and a variety of mental illnesses.
neurotrophin; growth factor; tropomyosin-related kinase receptor A; neurotrophic tyrosine kinase receptor 1; myelin; development; fractional anisotropy; radial diffusivity; diffusion tensor imaging; schizophrenia
The scaffolding protein IQGAP1 co-localizes with actin at the cytoplasmic face of the nuclear envelope: implications for cytoskeletal regulation
Johnson, Michael A.
Henderson, Beric R.
IQGAP1 is an important cytoskeletal regulator, known to act at the plasma membrane to bundle and cap actin filaments, and to tether the cortical actin meshwork to microtubules via plus-end binding proteins. Here we describe the novel subcellular localization of IQGAP1 at the cytoplasmic face of the nuclear envelope, where it co-located with F-actin. The IQGAP1 and F-actin staining overlapped that of microtubules at the nuclear envelope, revealing a pattern strikingly similar to that observed at the plasma membrane. In detergent-extracted cells IQGAP1 was retained at cytoskeletal structures at the nuclear envelope. This finding has new implications for involvement of IQGAP1 in cell polarization and migration events and potentially in cell cycle-associated nuclear envelope assembly/disassembly.
Cdc42; IQGAP1; Rac1; actin; cell polarization; nuclear envelope
A tethering complex dimer catalyzes trans-SNARE complex formation in intracellular membrane fusion
SNARE complexes mediate membrane fusion in the endomembrane system. They consist of coiled-coil bundles of four helices designated as Qa, Qb, Qc and R. A critical intermediate in the fusion pathway is the trans-SNARE complex generated by the assembly of SNAREs residing in opposing membranes. Mechanistic details of trans-SNARE complex formation and topology in a physiological system remain largely unresolved. Our studies on native yeast vacuoles revealed that SNAREs alone are insufficient to form trans-SNARE complexes and that additional factors, potentially tethering complexes and Rab GTPases, are required for the process. Here we report a novel finding that a HOPS tethering complex dimer catalyzes Rab GTPase-dependent formation of a topologically preferred QbQcR-Qa trans-SNARE complex.
HOPS tethering complex dimer; QbQcR-Qa trans-SNARE complex; Rab GTPase
Regulation of bi-directional movement of single kinesin-5 Cin8 molecules
Schmidt, Christoph F.
Kinesin-5 mechanoenzymes drive mitotic spindle dynamics as slow, processive microtubule (MT)-plus-end directed motors. Surprisingly, the Saccharomyces cerevisiae kinesin-5 Cin8 was recently found to be bi-directional: it can move processively in both directions on MTs. Two hypotheses have been suggested for the mechanism of the directionality switch: (1) single molecules of Cin8 are intrinsically minus-end directed, but mechanical coupling between two or more motors triggers the switch; (2) a single motor can switch direction, and “cargo binding” i.e., binding between two MTs triggers the switch to plus-end motility. Single-molecule fluorescence data we published recently, and augment here, favor hypothesis (2). In low-ionic-strength conditions, single molecules of Cin8 move in both minus- and plus-end directions. Fluorescence photo bleaching data rule out aggregation of Cin8 while they move in the plus and in the minus direction. The evidence thus points toward cargo regulation of directionality, which is likely to be related to cargo regulation in other kinesins. The molecular mechanisms of this regulation, however, remain to be elucidated.
Saccharomyces cerevisiae Cin8; kinesin directionality; kinesin-5; microtubules; mitosis
A novel role for the cytoskeletal linker protein dystonin in the maintenance of microtubule stability and the regulation of ER-Golgi transport
Ryan, Scott D.
Crosslinking proteins maintain organelle structure and facilitate their function through the crosslinking of cytoskeletal elements. We recently found an interaction between the giant crosslinking protein dystonin-a2 and the microtubule-associated protein-1B (MAP1B), occurring in the centrosomal region of the cell. In addition, we showed that this interaction is necessary to maintain microtubule acetylation. Loss of dystonin-a2 disrupts MT stability, Golgi organization, and flux through the secretory pathway. This, coupled to our recent finding that dystonin-a2 is critical in maintaining endoplasmic reticulum (ER) structure and function, provides novel insight into the importance of dystonin in maintenance of organelle structure and in facilitating intracellular transport. These results highlight the importance of cytoskeletal dynamics in communicating signals between organelle membranes and the cytoskeleton. Importantly, they demonstrate how defects in cytoskeletal dynamics can translate into a failure of vesicular trafficking associated with neurodegenerative disease.
Golgi; cytoskeleton; dystonin; endoplasmic reticulum; neuron; transport
TPM3 and TPM4 gene products segregate to the postsynaptic region of central nervous system synapses
Synaptic function in the central nervous system (CNS) is highly dependent on a dynamic actin cytoskeleton in both the pre- and the postsynaptic compartment. Remodelling of the actin cytoskeleton is controlled by tropomyosins, a family of actin-associated proteins which define distinct actin filament populations. Here we show that TPM3 and TPM4 gene products localize to the postsynaptic region in mouse hippocampal neurons. Furthermore our data confirm previous findings of isoform segregation to the pre- and postsynaptic compartments at CNS synapses. These data provide fundamental insights in the formation of functionally distinct actin filament populations at the pre- and post-synapse.
actin cytoskeleton; central nervous system; postsynapse; tropomyosin
Actin cytoskeleton dynamics lie at the heart of cell mechanosensing signaling. In fibroblast cells, two perinuclear acto-myosin structures, the actin cap and the transmembrane actin-associated nuclear (TAN) line, are components of a physical pathway transducing extracellular physical signals to changes in nuclear shape and movements. We recently demonstrated the existence of a previously uncharacterized third apical perinuclear actin organization in epithelial cells that forms during epithelial–mesenchymal transition (EMT) mediated by TGFβ (TGFβ). A common regulatory mechanism for these different perinuclear actin architectures has emerged with the identification of a novel family of actin bundling proteins, the Refilins. Here we provide updates on some characteristics of Refilin proteins, and we discuss potential function of the Refilins in cell mechanosensing signaling.
EMT; Epithelial Mesenchymal Transition; FAM101A; FAM101B; Filamin; LINC complex; RefilinA; RefilinB; TAN lines; actin cap
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