Microtubules and Growth Cones: Motors Drive the Turn

Kahn, Olga I.; Baas, Peter W.

doi:10.1016/j.tins.2016.04.009

Cited by 72 publications

(61 citation statements)

References 58 publications

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“…Microtubules (MTs) are polar constituents of the cell cytoskeleton, participate in growth cone steering and extension, and play a pivotal role in axon formation [41]. MT stability and dynamics are regulated by combined actions of several classes of intrinsic proteins, including acetylated a-tubulin (Ace-tubulin) and tyrosinated a-tubulin (tubulin) [42].…”

Section: Resultsmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

192

140

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Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p<0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.

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Section: Resultsmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

192

140

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“…Our previous studies indicate that both KIF15 and KIF11 act as brakes on axonal microtubule transport, and that these brakes are responsive to signaling cascades that regulate features of axonal growth and navigation. Axons presumably grow faster when either of these motors is inhibited because of greater mobility of short microtubules and also less compressive force on the longer microtubules 24 . A potential issue with KIF11 inhibition as therapy for nerve injury arises from studies indicating that axon navigation is impaired when KIF11 is suppressed 25 , because of KIF11’s role in regulating the amount of microtubule sliding into the growth cone.…”

Section: Discussionmentioning

confidence: 99%

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9‐mediated kif15 mutations accelerate axonal outgrowth during neuronal development and regeneration in zebrafish

Dong

Zhu

et al. 2018

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KIF15, the vertebrate kinesin-12, is best known as a mitotic motor protein, but continues to be expressed in neurons. Like KIF11 (the vertebrate kinesin-5), KIF15 interacts with microtubules in the axon to limit their sliding relative to one another. Unlike KIF11, KIF15 also regulates interactions between microtubules and actin filaments at sites of axonal branch formation and in growth cones. Our original work on these motors was done on cultured rat neurons, but we are now using zebrafish to extent these studies to an in vivo model. We previously studied kif15 in zebrafish by injecting splice-blocking morpholinos injected into embryos. Consistent with the cell culture work, these studies demonstrated that axons grow faster and longer when KIF15 levels are reduced. In the present study, we applied CRISPR/Cas9-based knockout technology to create kif15 mutants and labeled neurons with Tg(mnx1:GFP) transgene or transient expression of elavl3:EGFP-alpha tubulin. We then compared by live imaging the homozygotic, heterozygotic mutants to their wildtype siblings to ascertain the effects of depletion of kif15 during Caudal primary (CaP) motor neuron and Rohon-Beard (R-B) sensory neuron development. The results showed, compared to the kif15 wildtype, the number of branches was reduced while axon outgrowth was accelerated in kif15 homozygotic and heterozygotic mutants. In R-B sensory neurons, after laser irradiation, injured axons with loss of kif15 displayed significantly greater regenerative velocity. Given these results and the fact that kif15 drugs are currently under development, we posit kif15 as a novel target for therapeutically augmenting regeneration of injured axons.

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“…Axonal growth cones are highly motile structures involved in axon outgrowth and guidance (59,60). They comprise a central region enriched in microtubules and transport vesicles and a peripheral region with a high concentration of actin filaments that organize lamellipodia and filopodia.…”

Section: Borc-dependent Lysosome Transport Promotes Axonal Growth-conementioning

confidence: 99%

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

179

234

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The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

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Microtubules and Growth Cones: Motors Drive the Turn

Cited by 72 publications

References 58 publications

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9‐mediated kif15 mutations accelerate axonal outgrowth during neuronal development and regeneration in zebrafish

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

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