Altered microtubule organization in small-calibre axons of mice lacking tau protein

Harada, Akira; Oguchi, K; Okabe, Susumu; Kuno, Junko; Terada, Sumio; Ohshima, Toshiyuki; Sato-Yoshitake, Reiko; Takei, Yosuke; Noda, Tetsuo; Hirokawa, Nobutaka

doi:10.1038/369488a0

Cited by 690 publications

(577 citation statements)

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“…Structural distortions as a consequence of fixation with glutaraldehyde are unlikely as glutaraldehyde has been reported to cause structural distortions at high concentrations but not at low concentrations such as those used in the present study ([26]; and unpublished observation). It is interesting to note that the morphology of the microtubules observed with each MAP appears to closely resemble the description of microtubules in the neuronal regions in which these MAPs are concentrated [1,2,8,27,28]. MAP1A and MAP2, which bind to distinct sites and can co-localise on the same microtubules both in vitro and in vivo, give rise to straight microtubules of the type found in MAP2-rich dendrites and MAP1A-rich axons.…”

Section: Discussionmentioning

confidence: 63%

Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2

et al. 1996

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The effect of microtubule associated proteins on microtubule shape has been investigated in reconstitution experiments using purified tubulin and purified MAP1A, MAP1B, and MAP2. Microtubules assembled in the presence of these MAPs were fixed with 0.1% glutaraldehyde and, after negative staining, were examined by electron microscopy. The results show that MAP1A microtubules were generally short and 'straight' while those assembled with MAP1B were longer and 'bendy'. MAP2 microtubnies showed both types of morphologies even though straight microtubules were more abundant. These data suggest that MAPs may modulate not only microtubnie dynamics but also microtubule shape which may be important in their spatial distribution and/or role in specific neuronal areas.

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Section: Discussionmentioning

confidence: 63%

Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2

et al. 1996

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“…Based on the analysis of the phenotype of these animals, the authors claimed the existence of some synergic effects of the two proteins. It is worth noting that the double mutant animals were obtained by breeding a tau mutant line that overexpresses MAP1A in response to the tau deficiency (Harada et al, 1994) with a MAP1B hypomorphic mutant line (Takei et al, 1997). Therefore, this phenotype may not have an easy interpretation and this must be carefully taken into account.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that a functional redundancy might exist among MAPs (Harada et al, 1994;DiTella et al, 1996;Takei et al, 2000). Therefore, we looked for the existence of such a compensatory mechanism with the use of quantitative fluorescence to measure changes in the relative levels of MAP2 and tau, proteins that have been directly implicated in the regulation of microtubule dynamics and process outgrowth in developing neurons Kosik, 1990, 1992;Harada et al, 1994).…”

Section: Functional Redundancy In Neurons From Map1b-deficient Micementioning

confidence: 99%

“…Therefore, we looked for the existence of such a compensatory mechanism with the use of quantitative fluorescence to measure changes in the relative levels of MAP2 and tau, proteins that have been directly implicated in the regulation of microtubule dynamics and process outgrowth in developing neurons Kosik, 1990, 1992;Harada et al, 1994). No significant changes in the fluorescence intensity or distribution of MAP2 or tau immunostaining were detected between WT and MAP1B-deficient neurons when cells were fixed before detergent extraction ( Figure 7, A and B).…”

Section: Functional Redundancy In Neurons From Map1b-deficient Micementioning

confidence: 99%

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Evidence for the Role of MAP1B in Axon Formation

González-Billault

Ávila

Cáceres

2001

MBoC

134

138

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Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. INTRODUCTIONNeurons are highly polarized cells that contain a single long axon and multiple dendrites. Polarization occurs when one of the multiple neurites emerging from the cell body initiates a phase of rapid elongation, becoming the axon; the remaining neurites will develop as dendrites Dotti, 1997, 1999;Dotti et al., 1998). Because microtubule assembly and stabilization play an essential role in axon formation (Mitchison and Kirschner, 1989) a great deal of attention has been devoted to identify factors controlling microtubule organization and dynamics in nerve cells. Current evidence favors the view that several of the distinctive properties of neuronal microtubules, such as increased stability and spatial differentiation, arise from the developmentally regulated expression of structural microtubule-associated proteins (MAPs), which are notably abundant in neurons (Maccioni and Cambiazo, 1995). Therefore, it is likely that the expression of these proteins along neuronal development may affect neuronal polarization.MAP1B (Bloom et al., 1995) is the first MAP that is specifically expressed during neural development and that is especially prominent in neurons that are actively extending axons (Calvert and Anderton, 1985;Garner et al., 1990;Fischer and Romano-Clarke, 1991;Ulloa et al., 1993;Black et al., 1994: DiTella et al., 1996Gordon-Weeks and Fischer, 2000). These findings led to the hypothesis that MAP1B might be involved in axon formation by regulating microtubule dynamics. Evidence in favor of this proposal came from antisense experiments showing that MAP1B suppression reduces laminin-promoted axonal elongation (DiTella et al., 1996) and neurite outgrowth in PC12 cells (Brugg et al., 1993). More recently, it was shown that in Drosophila, an MAP1B-like protein is required for proper axonal and dendritic development Roos et al., 2000), and that microscale chromophore-assisted laser inactivation of phosphorylated MAP1B altered growth cone turning behavior in cultured neurons (Mack et al., 2000). The generation of MAP1B mutant mice has also provided additional important information. Despite discrepancies concerning the severity of the effects, all studies demonstrate that MAP1B-deficient mice have an impairment of brain development (Edelman et al., 1996;Takei et al., 1997; GonzalezBillault et...

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“…Four independent lines of full tau knockout mice have been generated prior to this study, and no significant behavioral or neuropathological phenotype has been reported (Dawson et al., 2010; Fujio et al., 2007; Harada et al., 1994; Ke et al., 2012; Tucker, Meyer & Barde, 2001). The relatively mild phenotype is likely due to compensatory events during development and to the redundancy associated with different microtubule‐binding proteins (Denk & Wade‐Martins, 2009; Ke et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

et al. 2018

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SummaryMisfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule‐binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule‐binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno‐associated virus (AAV) expressing a doxycycline‐inducible short‐hairpin (Sh) RNA targeted to tau, herein referred to as AAV‐ShRNATau. We performed bilateral stereotaxic injections in 7‐month‐old C57Bl6/SJL wild‐type mice with either the AAV‐ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV‐ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss‐of‐function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti‐tau therapies are in clinical trials for Alzheimer's disease.

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Altered microtubule organization in small-calibre axons of mice lacking tau protein

Cited by 690 publications

References 28 publications

Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2

Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2

Evidence for the Role of MAP1B in Axon Formation

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

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