Polarity Sorting of Microtubules in the Axon

Rao, Anand N.; Baas, Peter W.

doi:10.1016/j.tins.2017.11.002

Cited by 42 publications

(42 citation statements)

References 65 publications

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“…) a number of other motors also influences their transport, for example, by acting as brakes (Myers and Baas, 2007;Liu et al, 2010;Lin et al, 2012;Del Castillo et al, 2015). Acute inhibition of a molecular motor is the best way to reveal its role in microtubule transport given that prolonged depletion of a motor by RNAi can result in changes in the polarity orientation of both short mobile microtubules and the longer microtubules against which the short ones are transported and can also allow motors that normally do not transport short microtubules to do so (Rao and Baas, 2018). Our various studies have validated the smallmolecule inhibitors of KIFC1 as effective, specific, and nontoxic and thus are suitable to analyze the role of KIFC1 in the transport of short microtubules in the axon.…”

Section: Kifc1 Affects the Ratio Of Anterograde To Retrograde Transpomentioning

confidence: 99%

“…Several proteins contribute to the organization of microtubules in the axon. We have emphasized the importance of molecular motor proteins, not only in transporting microtubules within the axon (Baas and Ahmad, 2001;Baas, 2002;He et al, 2005;Ahmad et al, 2006;Baas et al, 2006;Myers and Baas, 2007;Liu et al, 2010;Lin et al, 2012;Rao et al, 2017), but also in imposing order on the microtubules (Rao and Baas, 2018) and orchestrating a variety of force-related mechanisms underlying events in the life of the neuron such as growth cone turning Nadar et al, 2008Nadar et al, , 2012Liu et al, 2010) and neuronal migration (Buster et al, 2003;Falnikar et al, 2011;Rao et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon

Muralidharan

Baas

2019

J. Neurosci.

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KIFC1 (also called HSET or kinesin-14a) is best known as a multifunctional motor protein essential for mitosis. The present studies are the first to explore KIFC1 in terminally postmitotic neurons. Using RNA interference to partially deplete KIFC1 from rat neurons (from animals of either gender) in culture, pharmacologic agents that inhibit KIFC1, and expression of mutant KIFC1 constructs, we demonstrate critical roles for KIFC1 in regulating axonal growth and retraction as well as growth cone morphology. Experimental manipulations of KIFC1 elicit morphological changes in the axon as well as changes in the organization, distribution, and polarity orientation of its microtubules. Together, the results indicate a mechanism by which KIFC1 binds to microtubules in the axon and slides them into alignment in an ATP-dependent fashion and then cross-links them in an ATP-independent fashion to oppose their subsequent sliding by other motors.Here, we establish that KIFC1, a molecular motor well characterized in mitosis, is robustly expressed in neurons, where it has profound influence on the organization of microtubules in a number of different functional contexts. KIFC1 may help answer long-standing questions in cellular neuroscience such as, mechanistically, how growth cones stall and how axonal microtubules resist forces that would otherwise cause the axon to retract. Knowledge about KIFC1 may help researchers to devise strategies for treating disorders of the nervous system involving axonal retraction given that KIFC1 is expressed in adult neurons as well as developing neurons.

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Section: Kifc1 Affects the Ratio Of Anterograde To Retrograde Transpomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon

Muralidharan

Baas

2019

J. Neurosci.

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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: 70%

“…This may be due to the "microtubule gatekeeper" role that dynein is proposed to play in maintaining axonal microtubule polarity. 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).…”

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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“…This means that the directionality of MTs networks directly influences the motor transport. Depending on the cell type, MT networks are either unipolar, with all the MTs oriented in the same direction as in the vertebrate axons, or have mixed directionality as in vertebrate dendrites or epithelial cells [36][37][38][39][40][41]. Additionally, MTs form bundles, where several MTs are closely apposed, often connected by specialized cross-linking proteins [42][43][44], and unidirectional bundles facilitate intracellular transport [45,46].…”

Section: Introductionmentioning

confidence: 99%

The walkoff effect: cargo distribution implies motor type in bidirectional microtubule bundles

Zhelezov

Bulgakova

Alfred

et al. 2019

Preprint

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Cells rely on molecular motors moving along an ever-shifting network of polymers (microtubules) for the targeted delivery of cell organelles to biologically-relevant locations. We present a stochastic model for a molecular motor stepping along a bidirectional bundle of microtubules, as well as a tractable analytical model. Using these models, we investigate how the preferred stepping direction of the motor (parallel or antiparallel to the microtubule growth, corresponding to kinesin and dynein motor families) quantitatively and qualitatively affects the cargo delivery. We predict which motor type is responsible for which cargo type, given the experimental distribution of cargo in the cell, and report experimental findings which support this guideline for motor classification.

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Polarity Sorting of Microtubules in the Axon

Cited by 42 publications

References 65 publications

Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon

Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon

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

The walkoff effect: cargo distribution implies motor type in bidirectional microtubule bundles

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