Overexpression of tau in a nonneuronal cell induces long cellular processes

Knops, Jeroen; Kosik, Kenneth S.; Lee, G.; Pardee, Joel D.; Cohen-Gould, Leona; McConlogue, Lisa

doi:10.1016/0962-8924(91)90114-o

Cited by 67 publications

(109 citation statements)

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“…We also found that tau decreases the rate and extent of microtubule growth in cells. These data are in contrast to the widely recognized ability of tau to promote microtubule growth and assembly under non-steady state conditions, both in vitro (Cleveland et al, 1977;Fellous et al, 1977) and in cells (Caceres and Kosik, 1990;Knops et al, 1991;Esmaeli-Azad et al, 1994; reviewed in Buee et al, 2000). They are also in contrast to the taumediated enhancement of the rate and extent of microtubule growth observed in dynamics studies in vitro, also under non-steady state conditions of net microtubule assembly (Drechsel et al, 1992;Trinczek et al, 1995).…”

mentioning

confidence: 62%

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Bunker

Wilson

Jordan

et al. 2004

MBoC

134

127

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The neural microtubule-associated protein tau binds to and stabilizes microtubules. Because of alternative mRNA splicing, tau is expressed with either 3 or 4 C-terminal repeats. Two observations indicate that differences between these tau isoforms are functionally important. First, the pattern of tau isoform expression is tightly regulated during development. Second, mutation-induced changes in tau RNA splicing cause neuronal cell death and dementia simply by altering the isoform expression ratio. To investigate whether 3-and 4-repeat tau differentially regulate microtubule behavior in cells, we microinjected physiological levels of these two isoforms into EGFP-tubulin-expressing cultured MCF7 cells and measured the effects on the dynamic instability behavior of individual microtubules by time-lapse microscopy. Both isoforms suppressed microtubule dynamics, though to different extents. Specifically, 4-repeat tau reduced the rate and extent of both growing and shortening events. In contrast, 3-repeat tau stabilized most dynamic parameters about threefold less potently than 4-repeat tau and had only a minimal ability to suppress shortening events. These differences provide a mechanistic rationale for the developmental shift in tau isoform expression and are consistent with a loss-of-function model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal cell death and dementia. INTRODUCTIONThe microtubule-associated protein tau promotes neuronal cell polarization and axonal outgrowth; it is also necessary for maintaining axonal morphology and axonal transport (Caceres and Kosik, 1990;Esmaeli-Azad et al., 1994;Trinczek et al., 1999;Stamer et al., 2002). Alternatively, abnormal tau is the major component of neurofibrillary tangles, hallmark pathological features of Alzheimer's disease and related dementias.Mechanistically, tau acts by binding to microtubules directly and regulating their growing, shortening, and treadmilling dynamics (Drechsel et al., 1992;Panda et al., 1995Panda et al., , 1999Trinczek et al., 1995). Because tight regulation of microtubule dynamics and microtubule behavior can be critical to cell viability (Jordan et al., 1996;Goncalves et al., 2001), fine regulation of tau activity may be equally critical.Tau activity is regulated in part by alternative mRNA splicing, which leads to the expression of two families of tau isoforms, those containing four C-terminal repeats and those with three such repeats ( Figure 1A; Lee et al., 1988;Himmler, 1989). In vitro studies have shown that 4-repeat tau binds to, assembles, and stabilizes microtubules more effectively than 3-repeat tau (Butner and Kirschner, 1991;Gustke et al., 1994;Trinczek et al., 1995;Goode et al., 2000;Panda et al., 2003). However, there are limited data assessing the abilities of 3-or 4-repeat tau to modulate dynamics in a complex cellular environment.The importance of functional differences between 3-and 4-repeat tau is highlighted by two observations. First, altho...

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mentioning

confidence: 62%

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Bunker

Wilson

Jordan

et al. 2004

MBoC

134

127

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“…In cultured cerebellar neurons, antisense oligonucleotides for MAP2 and tau inhibit the incorporation of tubulin monomers into microtubules and prevent neurite elongation respectively (Caceres and Kosik, 1990). In non-neuronal cells, such as Sf9 cells, transfection of tau or MAP cDNA changes the cells from a normal rounded shape to a polarized morphology with an unbranched and elongated process (Baas et al, 1991;Knops et al, 1991;Boucher et al, 1999;Bélanger et al, 2001). These results indicate that neurite outgrowth of axons and dendrites depends on the assembly of microtubules, and that the polarization of the transfected non-neuronal cells, even in the absence of neuronal signalling machinery, is caused by the expression of intracellular tau or MAP.…”

Section: Agentmentioning

confidence: 99%

Disassembly of actin filaments by botulinum C₂ toxin and actin‐filament‐disrupting agents induces assembly of microtubules in human leukaemia cell lines

Uematsu

Kogo

Ohishi

2007

Biology of the Cell

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Background information. C 2 toxin produced by Clostridium botulinum types C and D ADP-ribosylates actin monomers and inactivates their polymerization activities. The disassembly of actin filaments by C 2 toxin induces a polarization of cultured human leukaemia cell lines.Results. The polarization induced by C 2 toxin was temperature dependent and was prevented by nocodazole, a microtubule-disrupting agent, whereas it was promoted by paclitaxel, a microtubule-stabilizing agent. The fluorescence staining of polarized cells indicated an increase in microtubule assembly accompanying disassembly of actin filaments. Furthermore, several actin-filament-disrupting agents, other than C 2 toxin, also induced microtubule assembly and cell polarization, irrespective of their different mechanisms of action. The effects induced by some of the agents, which have lower binding affinities for actin, were reversible in response to the re-assembly of actin filaments.Conclusions. Thus the disassembly of actin filaments by C 2 toxin and actin-filament-disrupting agents induces assembly of microtubules followed by polarization of human leukaemia cell lines, indicating that the assembly/disassembly equilibrium of actin filaments influences the dynamics of microtubules, which control cell morphology and, in turn, diverse cellular processes.

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“…In normal neurons, tau associates with microtubules and promotes microtubule stability by suppressing dynamic instability. Tau protein has been implicated in numerous cellular processes, including neurite outgrowth [4,5,19], microtubule transport [11], and oligodendrocyte maturation [13,18]. When hyperphosphorylated, as in AD, tau protein self-aggregates to form NFTs.…”

Section: Introductionmentioning

confidence: 99%

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

Dunckley

Beach²,

Ramsey

et al. 2006

Neurobiology of Aging

159

134

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Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.

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Overexpression of tau in a nonneuronal cell induces long cellular processes

Cited by 67 publications

References 11 publications

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Disassembly of actin filaments by botulinum C₂ toxin and actin‐filament‐disrupting agents induces assembly of microtubules in human leukaemia cell lines

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

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Overexpression of tau in a nonneuronal cell induces long cellular processes

Cited by 67 publications

References 11 publications

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Disassembly of actin filaments by botulinum C2 toxin and actin‐filament‐disrupting agents induces assembly of microtubules in human leukaemia cell lines

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

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Disassembly of actin filaments by botulinum C₂ toxin and actin‐filament‐disrupting agents induces assembly of microtubules in human leukaemia cell lines