Axonal Transport: How High Microtubule Density Can Compensate for Boundary Effects in Small-Caliber Axons

Wortman, Juliana C.; Shrestha, Uttam; Barry, Devin M.; Garcia, Michael L.; Gross, Steven P.; Yu, Clare C.

doi:10.1016/j.bpj.2013.12.047

Cited by 39 publications

(48 citation statements)

References 78 publications

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“…Furthermore, the presence of these bounding membranes may make it difficult to push other objects out of the way because they have nowhere to move. Thus, theoretical studies suggest that cargos likely encounter varying levels of opposition, at least some of which depend on cargo size, with larger cargos subject to increased resistance to motion. Because Lis1 helps groups of dynein motors add forces productively , a study where Lis1 alteration particularly affected neuronal transport of large lysosomes is consistent with such a size‐dependent opposition hypothesis.…”

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confidence: 99%

A Biophysical Analysis of Mitochondrial Movement: Differences Between Transport in Neuronal Cell Bodies Versus Processes

Narayanareddy

Vartiainen

Hariri

et al. 2014

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There is increasing interest in factors that can impede cargo transport by molecular motors inside the cell. While potentially relevant (1), the importance of cargo size and sub-cellular location have received relatively little attention. Here we address these questions taking advantage of the fact that mitochondria—a common cargo—in Drosophila neurons exhibit a wide distribution of sizes. In addition, the mitochondria can be genetically marked with GFP making it possible to visualize and compare their movement in the cell bodies and processes of living cells. Using total internal reflection (TIRF) microscopy coupled with particle tracking and analysis, we quantified transport properties of GFP positive mitochondria as a function of their size and location. In neuronal cell bodies we find little evidence for significant opposition to motion, consistent with a previous study on lipid droplets (2). However, in the processes we observe an inverse relationship between mitochondrial size and velocity and run distances. This can be ameliorated via hypotonic treatment to increase process size, suggesting that motor mediated movement is impeded in this more confined environment. Interestingly, we also observe local mitochondrial accumulations in processes but not in cell bodies. Such accumulations do not completely block transport, but do increase the probability of mitochondria-mitochondria interactions. They are thus particularly interesting in relation to mitochondrial exchange of elements.

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confidence: 99%

A Biophysical Analysis of Mitochondrial Movement: Differences Between Transport in Neuronal Cell Bodies Versus Processes

Narayanareddy

Vartiainen

Hariri

et al. 2014

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“…Thirdly, the MT volume of many axons seems to be a well-regulated property. This is suggested by neuron type-specific axon diameters and MT densities (Wortman et al, 2014), and the fact that artificially slimmed axons (achieved through pulling) reconstitute their original diameters (Bray, 1984). How axon diameters are sensed and MT volume (i.e.…”

Section: The Importance Of Mt Dynamics In Axonsmentioning

confidence: 99%

A conceptual view at microtubule plus end dynamics in neuronal axons

Voelzmann

Hahn

Pearce

et al. 2016

Brain Research Bulletin

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“…Considering the spatial limitation exerted by the rigid axon membrane 12 , the trafficking of large cargoes is likely to be affected. In fact, a simulation study based on axon structure and intra-axonal microfluidic dynamics predicted that cargo trafficking was impeded by the friction from the axonal walls in small-calibre axons 13 . In line with this prediction, a correlation between axon diameter and axon trafficking was recently reported in Drosophila 14, 15 and rodent neurons 16, 17 .…”

Section: Introductionmentioning

confidence: 99%

“…Considering the spatial constriction exerted by the rigid and stable circumventing actin MPS (membrane-associated periodic cytoskeletal structures) (Abouelezz et al, 2019a; Qu et al, 2017; Zhang et al, 2017; Zhong et al, 2014), the trafficking of large cargoes is likely to be affected. In fact, a simulation study based on axon structure and intra-axonal microfluidic dynamics predicted that cargo trafficking was impeded by the friction from the axonal walls in small-calibre axons (Wortman et al, 2014). In line with this prediction, correlations between axon diameter and axon trafficking have been recently reported in Drosophila (Fan et al, 2017; Narayanareddy et al, 2014) and rodent neurons (Leite et al, 2016; Pesaresi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Radial contractility of Actomyosin-II rings facilitates cargo trafficking and maintains axonal structural stability following cargo-induced transient axonal expansion

Wang

Martin

et al. 2018

Preprint

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17Most mammalian neurons have a narrow axon, which constrains the passage of large 18 cargoes such as autophagosome as they can be larger than the axon diameter. Variations 19 in tension must therefore occur radially to facilitate changes in axonal diameter and 20 ensure efficient axoplasmic trafficking. Here, we reveal that the transit of diverse large 21 membrane-bound cargoes causes an acute, albeit transient, radial expansion of the 22 axonal diameter, which is immediately restored by constricting forces. We demonstrate 23 that non-muscle myosin II (NM-II) forms ~200 nm periodic structures, which associate 24 with axonal F-actin rings. Inhibition of NM-II activity with blebbistatin significantly 25 increases axon diameter without affecting the periodicity of either the F-actin rings or 26 NM-II. This sustained radial expansion significantly affects the trafficking speed, 27 directionality, and reduces the overall efficiency of long-range retrograde axonal 28 cargoes, eventually leading to focal axon swelling and cargo accumulation, which are 29 hallmarks of axonal degeneration. 30 31 between 0.64 m and 0.74 m 3 . In contrast, the size of axonal cargoes is highly variable, 42 encompassing autophagosomes (0.5-1.5 m) 5 , mitochondria (0.75-3 m) 6 and 43 endosomes (50 nm-1 m) 7 . Thus, the range of cargo sizes is comparable to, or 44 surprisingly even larger than some of the CNS axons themselves. This advocates for 45 the existence of radial contractility in the axons, which would allow the transient 46 expansion of axon calibre and facilitate the passage of large cargoes. Indeed, the 47 expansion of axonal diameter surrounding large cargoes, i.e. autophagosomes 8 or 48 mitochondria 9 , has been observed by super-resolution microscopy and 2D-electron 49 microscopy (EM) in both normal and degenerating axons 10, 11 . Considering the spatial 50 limitation exerted by the rigid axon membrane 12 , the trafficking of large cargoes is 51 likely to be affected. In fact, a simulation study based on axon structure and intra-axonal 52 microfluidic dynamics predicted that cargo trafficking was impeded by the friction from 53 the axonal walls in small-calibre axons 13 . In line with this prediction, a correlation 54 between axon diameter and axon trafficking was recently reported in Drosophila 14, 15 55 and rodent neurons 16, 17 . However, direct evidence showing whether and how axonal 56 radial contractility affects cargo trafficking is still lacking. 57 58We hypothesized that the underlying structural basis for axonal radial contractility is 59 the subcortical actomyosin network, which is organized into specialized structures 60 called membrane-associated periodic cytoskeletal structures (MPS), as revealed with 61 super-resolution microscopy along the shafts of mature axons 18 . F-actin, together with 62 adducin and spectrin, forms a subcortical lattice with a ~190 nm periodic interval 63 covering the majority of the axon length 18, 19 . The disrupting of axonal F-actin leads to 64 loss of MPS 20, 21 , whereas the dep...

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Axonal Transport: How High Microtubule Density Can Compensate for Boundary Effects in Small-Caliber Axons

Cited by 39 publications

References 78 publications

A Biophysical Analysis of Mitochondrial Movement: Differences Between Transport in Neuronal Cell Bodies Versus Processes

A Biophysical Analysis of Mitochondrial Movement: Differences Between Transport in Neuronal Cell Bodies Versus Processes

A conceptual view at microtubule plus end dynamics in neuronal axons

Radial contractility of Actomyosin-II rings facilitates cargo trafficking and maintains axonal structural stability following cargo-induced transient axonal expansion

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