Global Up-Regulation of Microtubule Dynamics and Polarity Reversal during Regeneration of an Axon from a Dendrite

Stone, Michelle C.; Nguyen, Michelle M.; Tao, Juan; Allender, Dana L.; Rolls, Melissa M.

doi:10.1091/mbc.e09-11-0967

Cited by 117 publications

(186 citation statements)

References 39 publications

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“…It would be interesting to extend this observation by studying the effect of other AIS perturbations, because it suggests a massive effect of AIS disassembly on MT dynamics at the whole-cell level. Interestingly, up-regulation of EB proteins caused by ankG depletion is similar to the effect of in vivo axotomy in Drosophila neurons (27), demonstrating the profound consequences of AIS disassembly on neuronal polarity.…”

Section: Discussionmentioning

confidence: 82%

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

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

148

152

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The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments. In mature neurons, EB3 is concentrated and stabilized in the AIS. We identified a direct interaction between EB3/EB1 and the AIS scaffold protein ankyrin G (ankG). In addition, EB3 and EB1 participate in AIS maintenance, and AIS disassembly through ankG knockdown leads to cell-wide up-regulation of EB3 and EB1 comets. Thus, EB3 and EB1 coordinate a molecular and functional interplay between ankG and the AIS MTs that supports the central role of ankG in the maintenance of neuronal polarity. N eurons are highly polarized cells that rely on microtubules (MTs) for maintenance of their architecture and long-range polarized trafficking (1). MTs supporting axonal transport travel through the axon initial segment (AIS), a compartment that is essential for the generation of action potentials (2) and the maintenance of neuronal polarity (3). Generation of action potentials depends on the concentration of voltage-gated sodium (Nav) and potassium channels at the AIS, which are tethered at the plasma membrane via their interaction with ankyrin G (ankG (4-7). ankG, in turn, is linked to the actin cytoskeleton via βIV-spectrin and organizes AIS formation by recruiting membrane proteins and βIV-spectrin to the nascent AIS (3).The AIS maintains neuronal polarity by forming a diffusion barrier for membrane constituents at the cell surface (4,8,9) and also by dampening intracellular diffusion and vesicular transport through the AIS (10). Both phenomena depend on ankG, because depletion of ankG results in the disappearance of AIS and the acquisition of dendritic identity by the proximal axon (11,12). However, the molecular role of ankG in the intracellular AIS organization is still unknown. The dependence of the AIS intracellular filter on ankG (10) and the disorganization of MT bundles in the AIS of Purkinje cells from ankG-deficient mice (12) suggest an unknown link between ankG and MTs in the AIS.The end-binding (EB) proteins family, composed of three members (EB1-3), has been described as plus-end-tracking proteins (+TIPs) that coordinate a network of dynamic proteins on the growing MT plus-ends (13). In neurons, EB1 has been implicated in axonal transport (14, 15), whereas EB3 has been characterized as a molecular link between MTs and the actin cytoskeleton (16, 17). We hypothesized that EB proteins could have a role in the AIS via interaction with the ankG/βIV-spectrin scaffold. We first found that EB3 is accumulated and stabilized in the AIS of mature neurons. Both EB3 and EB1 bind to ankG and participate in the maintenance of the AIS scaffold. Reciprocally, altering neuronal polarity through ankG knockdown in...

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Section: Discussionmentioning

confidence: 82%

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

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

148

152

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“…We found previously that the number of growing microtubules is up-regulated in dendrites after axon injury (6). To test whether this change in microtubule dynamics might be related to dendrite stabilization, we compared the timing of these two responses.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, its neighbor, at right, has an elaborate dendrite arbor. a microtubule polymerase (13), and RNAi targeting msps eliminates EB1-GFP comets in neurons (6). We therefore used msps RNAi to perturb the behavior of neuronal microtubule plus ends.…”

Section: Resultsmentioning

confidence: 99%

“…For example, in mammalian dorsal root ganglion cells, injury of the peripheral axon causes a transcriptional response that increases the capacity of the central axon to regenerate if it is subsequently injured (4,5). In Drosophila sensory neurons, axon injury causes cytoskeletal changes in the entire dendrite arbor, specifically the number of growing microtubules is up-regulated (6). In this study, we investigated the functional significance of the cytoskeletal changes in the dendrite arbor.…”

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confidence: 99%

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Axon injury and stress trigger a microtubule-based neuroprotective pathway

Chen

Stone

Tao

et al. 2012

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

Self Cite

102

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Axon injury elicits profound cellular changes, including axon regeneration. However, the full range of neuronal injury responses remains to be elucidated. Surprisingly, after axons of Drosophila dendritic arborization neurons were severed, dendrites were more resistant to injury-induced degeneration. Concomitant with stabilization, microtubule dynamics in dendrites increased. Moreover, dendrite stabilization was suppressed when microtubule dynamics was dampened, which was achieved by lowering levels of the microtubule nucleation protein γ-tubulin. Increased microtubule dynamics and global neuronal stabilization were also activated by expression of expanded polyglutamine (poly-Q) proteins SCA1, SCA3, and huntingtin. In all cases, dynamics were increased through microtubule nucleation and depended on JNK signaling, indicating that acute axon injury and long-term neuronal stress activate a common cytoskeleton-based stabilization program. Reducing levels of γ-tubulin exacerbated long-term degeneration induced by SCA3 in branched sensory neurons and in a well established Drosophila eye model of poly-Q-induced neurodegeneration. Thus, increased microtubule dynamics can delay short-term injury-induced degeneration, and, in the case of poly-Q proteins, can counteract progressive longer-term degeneration. We conclude that axon injury or stress triggers a microtubulebased neuroprotective pathway that stabilizes neurons against degeneration.M any animals generate a single set of neurons that must function for the entire life of the individual. Each neuron typically has a single axon that transmits signals to other neurons or output cells such as muscle. As axons can extend long distances, they are at risk for injury, and, if the single axon is damaged, the cell can no longer function. Many neurons thus mount major responses to axon injury. The best characterized of these responses is axon regeneration, the process in which a neuron extends the stump of the existing axon or grows a new axon from a dendrite (1-3).In addition to the regenerative response, axon injury can cause other less well-understood changes. For example, in mammalian dorsal root ganglion cells, injury of the peripheral axon causes a transcriptional response that increases the capacity of the central axon to regenerate if it is subsequently injured (4, 5). In Drosophila sensory neurons, axon injury causes cytoskeletal changes in the entire dendrite arbor, specifically the number of growing microtubules is up-regulated (6). In this study, we investigated the functional significance of the cytoskeletal changes in the dendrite arbor. We present results that suggest the altered microtubule dynamics in dendrites acts to stabilize them, and thus axon injury seems to trigger a neuroprotective pathway that acts on the rest of the cell. However, this neuroprotective pathway is turned on only transiently after axon injury and subsides as axon regeneration initiates.Axon injury is a very acute neuronal stress. Neurons are also subject to a variety of long-term stress...

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“…According to Stone et al [7], this suggests that minus-end-out rather than mixed MT polarity orientation may be a signature of the dendritic cytoskeleton. There are also some interesting studies on the ability of Drosophila neurons to regenerate after trauma, such as after complete axon removal (Stone et al [11]). It has been shown that regeneration in this case involves complete MT polarity reversal in one dendrite that is later converted to an axon.…”

mentioning

confidence: 99%

Modeling transport of a pulse of radiolabeled organelles in a Drosophila unipolar motor neuron

Кузнецов

2012

J Biol Phys

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Based on published experimental evidence, this paper develops a model for the transport of a pulse of radiolabeled organelles in a unipolar Drosophila motor neuron. In particular, since published data indicate that no microtubules (MTs) travel from the primary neurite into the dendrite, it is investigated how organelles are transported into the dendrite. Analytical solutions describing concentrations of kinesin-and dynein-driven organelles in the primary neurite, axon, and dendrite are obtained. The effects of increasing the width of the pulse and increasing the rate of organelle transition rate from the kinesin-driven to the dynein-driven state are investigated.

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Global Up-Regulation of Microtubule Dynamics and Polarity Reversal during Regeneration of an Axon from a Dendrite

Abstract: We look inside neurons in vivo and identify major cytoskeletal rearrangements that allow a dendrite to become a regenerating axon.

Cited by 117 publications

References 39 publications

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Axon injury and stress trigger a microtubule-based neuroprotective pathway

Modeling transport of a pulse of radiolabeled organelles in a Drosophila unipolar motor neuron

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