MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells

Tortosa, Elena; Galjart, Niels; Ávila, Jesús; Sayas, Carmen Laura

doi:10.1038/emboj.2013.76

Cited by 78 publications

(94 citation statements)

References 49 publications

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“…4D, Movie S3, clips 1 and 2, respectively, and Table S3); however, the Pk pkexpressing larvae showed a significant increase in the length of the EB1-GFP comets compared to control larvae (Mann-Whitney U, P < 0.0001; Fig. 4E), demonstrating that there is an increase in MT plus-end polymerization when the balance is tipped in favor of the Pk pk isoform (22,23). In neurons expressing the Pk sple isoform, a large fraction of the MTs were actually reversed in orientation, with 36% of the comets moving toward the cell body and 64% of the comets moving toward the nerve terminal (Fig.…”

Section: Resultsmentioning

confidence: 99%

prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies

Ehaideb

Iyengar

Ueda³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Recent analyses in flies, mice, zebrafish, and humans showed that mutations in prickle orthologs result in epileptic phenotypes, although the mechanism responsible for generating the seizures was unknown. Here, we show that Prickle organizes microtubule polarity and affects their growth dynamics in axons of Drosophila neurons, which in turn influences both anterograde and retrograde vesicle transport. We also show that enhancement of the anterograde transport mechanism is the cause of the seizure phenotype in flies, which can be suppressed by reducing the level of either of two Kinesin motor proteins responsible for anterograde vesicle transport. Additionally, we show that seizure-prone prickle mutant flies have electrophysiological defects similar to other fly mutants used to study seizures, and that merely altering the balance of the two adult prickle isoforms in neurons can predispose flies to seizures. These data reveal a previously unidentified pathway in the pathophysiology of seizure disorders and provide evidence for a more generalized cellular mechanism whereby Prickle mediates polarity by influencing microtubule-mediated transport.epilepsy | planar cell polarity | spiny-legs | EB1-GFP | neurodegeneration E pilepsy, which affects ∼1% of the population, is a disabling and debilitating disease characterized by recurrent seizures. Coupling genetic analysis of human epilepsy cases with functional validation in animal models, we previously showed that mutations in human PRICKLE1 and PRICKLE2, as well as mutations in mouse, zebrafish and fly prickle (pk) orthologs, increase susceptibility to seizures (1-3). We recently showed that both mouse and fly Prickle can associate with Synapsin (4). However, little is known regarding what cellular process connects Prickle with epilepsy. Products of the prickle gene work in concert with a group of cytoplasmic and membrane-associated proteins including Frizzled (Fz) and Dishevelled (Dsh) to establish polarity of structures such as hairs and bristles in the fly epidermis (5-8). The fly pk locus expresses three alternately spliced isoforms, two of which, pk sple (prickle-spiny-legs) and pk pk (prickle-prickle), are expressed in postembryonic animals (5, 7). Homozygous pk pk and pk sple fly mutants show strong planar cell polarity (PCP) phenotypes in the wing and in the legs, respectively, in addition to other regions of the adult body (6, 7). Prickle (Pk) protein isoforms are localized to the proximal end of fly wing cells, whereas Fz and Dsh are localized distally (8).Here, we show that vesicle transport dynamics are altered in neurons of Drosophila mutant for either adult isoform of prickle. Seizure-prone pk sple heterozygotes show enhanced vesicle transport (along with electrophysiological defects similar to other seizure-prone mutant flies), and the seizure phenotypes can be rescued by lowering the dose of vesicle transport motor proteins. However, pk pk heterozygotes show severely reduced vesicle transport, with loss of both copies of pk pk showing a marked decrease i...

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Section: Resultsmentioning

confidence: 99%

prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies

Ehaideb

Iyengar

Ueda³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…40 Moreover, expression of EB1/3 and MAP1B is enriched along extending neurites and axons. 10 As shown in the model presented in Figure 1A, we have recently shown that MAP1B interacts directly with EB1/3 and sequesters them in the cytosol of developing neuronal cells thereby regulating MT dynamics in a coordinated fashion. 10 We propose that MAP1B reduces the effective pool of cytosolic EBs available to interact with MT plusends, thus keeping the high MT dynamicity required during axonogenesis.…”

Section: Map1b Sequesters Ebs In the Cytosol Of Extending Neurites/axmentioning

confidence: 99%

“…10 As shown in the model presented in Figure 1A, we have recently shown that MAP1B interacts directly with EB1/3 and sequesters them in the cytosol of developing neuronal cells thereby regulating MT dynamics in a coordinated fashion. 10 We propose that MAP1B reduces the effective pool of cytosolic EBs available to interact with MT plusends, thus keeping the high MT dynamicity required during axonogenesis. In particular, the MAP1B/EBs crosstalk in growth cones contributes to growth cone remodeling and proper advance during axon outgrowth.…”

Section: Map1b Sequesters Ebs In the Cytosol Of Extending Neurites/axmentioning

confidence: 99%

“…Notably, these studies show that classical MAPs act as direct regulators of the actions of EBs in neuronal cells, pointing to the existence of a functional interplay between these two types of microtubular proteins. 10,11 Typical localization of classical MAPs and EBs on MTs differ: while EBs accumulate at MT plus-ends in a comet-like pattern, classical MAPs bind along MTs. 7,9 How can then EBs be directly regulated by MAPs?…”

Section: Maps As Modulators Of Ebs Actions In Neuronsmentioning

confidence: 99%

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Regulation of EB1/3 proteins by classical MAPs in neurons

Sayas

Ávila

2014

BioArchitecture

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“…Some of them, like tau or MAP2, induce MT bundling, whereas others like MAP4 do not have bundling activity (Burgin et al 1994;Kanai et al 1989Nguyen et al 1997;Olson et al 1995). In addition, MAP1B has been shown to control MT dynamic, while MAP4 alters MT surface properties and affects motor protein activity Samora et al 2011;Semenova et al 2014;Tokuraku et al 2007;Tortosa et al 2013;Utreras et al 2008). Interestingly, many of these MAPs not only bind MTs but also interact with actin and participate in numerous signal pathways.…”

Section: Classical Mapsmentioning

confidence: 99%

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

2016

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Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity. IntroductionMicrotubules (MTs) are cytoskeletal structures that play essential roles in all eukaryotic cells. MTs are important not only during cell division but also in non-dividing cells, where they are critical structures in numerous cellular processes such as cell motility, migration, differentiation, intracellular transport and organelle positioning. MTs are composed of two proteins, α-and β-tubulin, that form heterodimers and organize themselves in a head-to-tail manner. MTs are dynamic and they can rapidly switch between cycles of growth and shrinkage. This MT

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MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells

Cited by 78 publications

References 49 publications

prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies

prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies

Regulation of EB1/3 proteins by classical MAPs in neurons

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

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