Cytoplasmic Dynein Transports Axonal Microtubules in a Polarity-Sorting Manner

Rao, Anand N.; Patil, Ankita; Black, Mark M.; Craig, Erin M.; Myers, Kenneth A.; Yeung, Howard; Baas, Peter W.

doi:10.1016/j.celrep.2017.05.064

Cited by 72 publications

(95 citation statements)

References 35 publications

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“…In support of this model, recent work has demonstrated that after 24 and 48 hours of dynein inhibition with ciliobrevin D, microtubule polarity in rat neurons becomes progressively less organized. 63 Further work with continued observation of microtubule growth and orientation over longer periods following dynein inhibition will be necessary to fully confirm the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

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

Klinman

Tokito

Holzbaur

2017

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The unique polarization of neurons depends on selective sorting of axonal and somatodendritic cargos to their correct compartments. Axodendritic sorting and filtering occurs within the axon initial segment (AIS). However, the underlying molecular mechanisms responsible for this filter are not well understood. Here, we show that local activation of the neuronal-specific kinase CDK5 is required to maintain AIS integrity, as depletion or inhibition of CDK5 induces disordered microtubule polarity and loss of AIS cytoskeletal structure. Furthermore, CDK5-dependent phosphorylation of the dynein regulator Ndel1 is required for proper re-routing of mislocalized somatodendritic cargo out of the AIS; inhibition of this pathway induces profound mis-sorting defects. While inhibition of the CDK5-Ndel1-Lis1-dynein pathway alters both axonal microtubule polarity and axodendritic sorting, we found that these defects occur on distinct timescales; brief inhibition of dynein disrupts axonal cargo sorting before loss of microtubule polarity becomes evident. Together, these studies identify CDK5 as a master upstream regulator of trafficking in vertebrate neurons, required for both AIS microtubule organization and polarized dynein-dependent sorting of axodendritic cargos, and support an ongoing and essential role for dynein at the AIS.

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Section: Discussionmentioning

confidence: 99%

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

Klinman

Tokito

Holzbaur

2017

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“…For example, neurofilaments, which provide structural stability to a cell, are transported to the axon terminus by plus end-directed microtubule motors (kinesins 4 ) and to the soma by the minus end-directed microtubule motor, cytoplasmic dynein (hereafter referred to as dynein) [5][6][7] . Dynein has also been shown to play a key role in trafficking numerous other neuronal cargoes in various model organisms [5][6][7][8][9][10][11][12][13][14][15][16][17][18] , including autophagosomes [19][20][21] , mitochondria, and ionotropic glutamate receptors 22 . Defects or perturbations in dynein function lead to mislocalization of these cargoes, and results in an accumulation of protein aggregates at the neurite tip 19,23 .…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

Marzo

Griswold

Ruff

et al. 2019

Preprint

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Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These "dyneinopathies" define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To overcome complications associated with studying dynein function in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we have determined the molecular basis for several broad classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we have alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein complexes. In addition to revealing molecular insight into dynein regulation, our data reveal an unexpected correlation between the degree of dynein dysfunction and disease type.3

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“…In addition to carrying cargo, dynein also transports, or slides, microtubules (Rao and Baas, 2018). Dynein anchored in the proximal axon translocates microtubules into or out of the axon and prevents the entry of minus-enddistal microtubules (del Castillo et al, 2015;Rao and Baas, 2018;Rao et al, 2017). Our data suggest that dynein also maintains axonal microtubule polarity by excluding Golgi outposts that have the capacity to induce changes in microtubule organization.…”

Section: Loss Of Gm130 Significantly Reduces Misoriented Microtubulesmentioning

confidence: 71%

“…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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Cytoplasmic Dynein Transports Axonal Microtubules in a Polarity-Sorting Manner

Cited by 72 publications

References 35 publications

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

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

Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

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

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