CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

Klinman, Eva; Tokito, Mariko; Holzbaur, Erika L.F.

doi:10.1111/tra.12529

Cited by 47 publications

(42 citation statements)

References 74 publications

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“…Consistent with previous studies (77–79), we have demonstrated that CCT acted on CDK5 to modulate retrograde axonal transport. It is possible that CDK5 signals through a mechanism involving dynein regulators Ndel1/Lis1 to stimulate retrograde axonal transport (77).…”

Section: Discussionsupporting

confidence: 93%

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Chen

Fang

Florio

et al. 2018

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The cytosolic chaperonin T-complex protein (TCP) 1-ring complex (TRiC) has been shown to exert neuroprotective effects on axonal transport through clearance of mutant Huntingtin (mHTT) in Huntington's disease. However, it is presently unknown if TRiC also has any effect on axonal transport in wild-type neurons. Here, we examined how TRiC impacted the retrograde axonal transport of brain-derived neurotrophic factor (BDNF). We found that expression of a single TRiC subunit significantly enhanced axonal transport of BDNF, leading to an increase in instantaneous velocity with a concomitant decrease in pauses for retrograde BDNF transport. The transport enhancing effect by TRiC was dependent on endogenous tau expression because no effect was seen in neurons from tau knockout mice. We showed that TRiC regulated the level of cyclin-dependent kinase 5 (CDK5)/p35 positively, contributing to TRiC-mediated tau phosphorylation (ptau). Expression of a single TRiC subunit increased the level of ptau while downregulation of the TRiC complex decreased ptau. We further demonstrated that TRiC-mediated increase in ptau induced detachment of tau from microtubules. Our study has thus revealed that TRiC-mediated increase in tau phosphorylation impacts retrograde axonal transport.

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Section: Discussionsupporting

confidence: 93%

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Chen

Fang

Florio

et al. 2018

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“…In the proximal axon of fly sensory neurons, Golgi outposts co-localize with the dynein co-factor NudE, which likely functions with dynein to localize outposts to dendrites (Arthur et al, 2015;Lin et al, 2015;Ye et al, 2007;Zheng et al, 2008). The mammalian NudE ortholog Ndel1 is proposed to "catch" dendritic cargos and prime them for dynein-mediated transport into dendrites (Klinman et al, 2017;Kuijpers et al, 2016). We found that simultaneously decreasing dynein activity and kinesin-1 autoinhibition resulted in ectopic axonal Golgi outposts.…”

Section: Discussionmentioning

confidence: 83%

Autoinhibition of kinesin-1 is essential to the dendrite-specific localization of Golgi outposts

Kelliher

Yue

et al. 2018

Preprint

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SummaryNeuronal polarity relies on the axon-or dendrite-specific localization of cargo by molecular motors such as kinesin-1. These studies show autoinhibition regulates both kinesin-1 activity and localization to keep dendritic cargo from entering axons. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/275149 doi: bioRxiv preprint first posted online 1 AbstractNeuronal polarity relies on the selective localization of cargo to axons or dendrites. The molecular motor kinesin-1 moves cargo into axons but is also active in dendrites. This raises the question of how kinesin-1 activity is regulated to maintain the compartment-specific localization of cargo. Our in vivo structure-function analysis of endogenous Drosophila kinesin-1 reveals a novel role for autoinhibition in enabling the dendrite-specific localization of Golgi outposts.Mutations that disrupt kinesin-1 autoinhibition result in the axonal mislocalization of Golgi outposts. Autoinhibition also regulates kinesin-1 localization. Uninhibited kinesin-1 accumulates in axons and is depleted from dendrites, correlating with the change in outpost distribution and dendrite growth defects. Genetic interaction tests show that a balance of kinesin-1 inhibition and dynein activity is necessary to localize Golgi outposts to dendrites and keep them from entering axons. Our data indicate that kinesin-1 activity is precisely regulated by autoinhibition to achieve the selective localization of dendritic cargo.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…The loss of dynein activity alters both Golgi outpost localization and axonal microtubule polarity (Arthur et al, 2015;del Castillo et al, 2015;Klinman et al, 2017;Rao et al, 2017;Zheng et al, 2008). We first asked whether the misoriented microtubules in dynein loss-of-function neurons depend on the ectopic Golgi outposts.…”

Section: Loss Of Gm130 Significantly Reduces Misoriented Microtubulesmentioning

confidence: 99%

Golgi outposts locally regulate microtubule orientation in neurons but are not required for the overall polarity of the dendritic cytoskeleton

Yang

Wildonger

2019

Preprint

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ABSTRACTMicrotubule-organizing centers (MTOCs) often play a central role in organizing the cellular microtubule networks that underlie cell function. In neurons, microtubules in axons and dendrites have distinct polarities. Dendrite-specific Golgi outposts, in particular multi-compartment outposts, have emerged as regulators of acentrosomal microtubule growth, raising the question of whether outposts contribute to establishing the overall polarity of the dendritic microtubule cytoskeleton. The cis-Golgi matrix protein GM130 has roles in both the MTOC activity of Golgi and in connecting Golgi compartments to form multi-compartment units. Using a combination of genetic approaches and live imaging in a Drosophila model, we found that GM130 is not essential for the overall polarity of the dendritic microtubule cytoskeleton. However, the mislocalization of multi-compartment Golgi outposts to axons disrupts the uniform orientation of axonal microtubules. This suggests that outposts have the capacity to influence microtubule polarity and, as our data indicate, likely do so independently of microtubule nucleation mediated by the γ-tubulin ring complex (γ-TuRC). Altogether, our results are consistent with the model that multi-compartment Golgi outposts may locally influence microtubule polarity, but that outposts are not necessary for the overall polarity of the dendritic microtubule cytoskeleton.

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CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

Cited by 47 publications

References 74 publications

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Autoinhibition of kinesin-1 is essential to the dendrite-specific localization of Golgi outposts

Golgi outposts locally regulate microtubule orientation in neurons but are not required for the overall polarity of the dendritic cytoskeleton

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