Extreme Stretch Growth of Integrated Axons

Pfister, Bryan J.; Iwata, Atsushi; Meaney, David F.; Smith, Douglas H.

doi:10.1523/jneurosci.1974-04.2004

Cited by 241 publications

(261 citation statements)

References 28 publications

(31 reference statements)

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“…Under an acute imposed stretch, the axonal cytoskeleton deforms elastically when the tension is high (18). Here, the imposed stretch rate is assumed to be much higher than the possible rate of growth of the axon under an applied stretch (25). With the stretch sustained, F-actin possibly slides with respect to each other giving rise to a relaxation of the tension.…”

Section: Discussionmentioning

confidence: 99%

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Siechen¹,

Yang

Chiba

et al. 2009

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

156

145

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Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynaptic cell. Our in vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored when mechanical tension is applied to the severed end of the axon. Clustering increases when intact axons are stretched mechanically by pulling the postsynaptic muscle. Using micro mechanical force sensors, we find that embryonic axons that have formed neuromuscular junctions maintain a rest tension of Ϸ1 nanonewton. If the rest tension is perturbed mechanically, axons restore the rest tension either by relaxing or by contracting over a period of Ϸ15 min. Our results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation and synaptic plasticity.T he accumulation of neurotransmitter containing vesicles at the presynaptic terminal is essential for neural communication. On the arrival of an action potential at the terminal, neurotransmitters are released through exocytosis of the vesicles. The transmitters excite the postsynaptic terminal in a millisecond time frame (1). The amount of neurotransmitter release for a given action potential depends on several factors including how frequently the synapse has been used. This usage dependent plasticity is believed to be the basis of memory and learning (2). Despite a wealth of knowledge on the molecular components of the synapse (3, 4) and the modulation of the postsynaptic machinery during long-term potentiation and depression (5-7), the mechanism of vesicle accumulation at the presynaptic terminal and regulation of neurotransmission in a usage-dependent manner remains unclear (8). There is increasing experimental evidence suggesting that the mechanical microenvironment has a significant influence on a variety of cell functions including gene expression, cell growth and morphology, cytoskeletal organization, and apoptosis (9-13). Our in vivo experiments reveal that mechanical tension in axons plays a key role in vesicle accumulation.We examine the neuromuscular synapse within live embryos of Drosophila melanogaster (14) (Fig. 1A). In Drosophila, an aCC (anterior corner cell) pioneer motoneuron extends a single axon and invariably innervates its target, muscle1. A pair of aCC motoneurons occurs in every segment of the embryo, and their development is highly stereotyped. The first contact between the aCC axon and muscle1 occurs at hour 14 of embryogenesis, ...

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Section: Discussionmentioning

confidence: 99%

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Siechen¹,

Yang

Chiba

et al. 2009

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

156

145

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“…During development, axons may reach targets, such as the neuromuscular junction (NMJ), by mid-embryonic stages. The majority of the axon growth may later be achieved via mechanical stretch (Pfister et al 2004) as growth of the body occurs, a process independent of growth cone motility. In contrast, during regeneration, the growth cone has to traverse the entire distance and must be regulated by growth mechanisms that do not involve stretch.…”

Section: Axon Regenerationmentioning

confidence: 99%

Intracellular control of developmental and regenerative axon growth

Zhou

Snider

2006

Phil. Trans. R. Soc. B

174

138

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Axon growth is a highly regulated process that requires stimulating signals from extracellular factors. The extracellular signals are then transduced to regulate coordinately gene expression and local axon assembly. Growth factors, especially neurotrophins that act via receptor tyrosine kinases, have been heavily studied as extracellular factors that stimulate axon growth. Downstream of receptor tyrosine kinases, recent studies have suggested that phosphatidylinositol-3 kinase (PI3K) regulates local assembly of axonal cytoskeleton, especially microtubules, via glycogen synthase kinase 3b (GSK-3b) and multiple microtubule binding proteins. The role of extracellular signal regulated kinase (ERK) signalling in regulation of local axon assembly is less clear, but may involve the regulation of local protein translation. Gene expression during axon growth is regulated by transcription factors, among which cyclic AMP response element binding protein and nuclear factors of activated T-cells (NFATs) are known to be required for neurotrophin (NT)-induced axon extension. In addition to growth factors, extracellular matrix molecules and neuronal activity contribute importantly to control axon growth. Increasingly, evidence suggests that these influences act to enhance growth via coordinating with growth factor signalling. Finally, evidence is emerging that developmental versus regenerative axon growth may be mediated by distinct signalling pathways, both at the level of gene transcription and at the level of local axon assembly.

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“…33 It has also been shown that moderate tensile loads can accelerate neuronal growth, both in vitro and in vivo. [34][35][36][37][38][39] Toward the development of more effective nerve regeneration strategies, in this study, we detail the design, fabrication, and preliminary implementation of a novel internal fixator device. This modular device, by imposing mechanical loads on regenerating nerves in parallel with existing tissue engineering strategies for nerve repair, facilitates two regimes of nerve extension-traditional extension through axonal outgrowth into an engineered scaffold and novel extension of intact regions of the proximal nerve (Fig.…”

Section: Introductionmentioning

confidence: 99%

A Novel Internal Fixator Device for Peripheral Nerve Regeneration

Chuang

Wilson

Love

et al. 2013

Tissue Engineering Part C: Methods

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Recovery from peripheral nerve damage, especially for a transected nerve, is rarely complete, resulting in impaired motor function, sensory loss, and chronic pain with inappropriate autonomic responses that seriously impair quality of life. In consequence, strategies for enhancing peripheral nerve repair are of high clinical importance. Tension is a key determinant of neuronal growth and function. In vitro and in vivo experiments have shown that moderate levels of imposed tension (strain) can encourage axonal outgrowth; however, few strategies of peripheral nerve repair emphasize the mechanical environment of the injured nerve. Toward the development of more effective nerve regeneration strategies, we demonstrate the design, fabrication, and implementation of a novel, modular nerve-lengthening device, which allows the imposition of moderate tensile loads in parallel with existing scaffold-based tissue engineering strategies for nerve repair. This concept would enable nerve regeneration in two superposed regimes of nerve extension-traditional extension through axonal outgrowth into a scaffold and extension in intact regions of the proximal nerve, such as that occurring during growth or limb-lengthening. Self-sizing silicone nerve cuffs were fabricated to grip nerve stumps without slippage, and nerves were deformed by actuating a telescoping internal fixator. Poly(lactic co-glycolic) acid (PLGA) constructs mounted on the telescoping rods were apposed to the nerve stumps to guide axonal outgrowth. Neuronal cells were exposed to PLGA using direct contact and extract methods, and they exhibited no signs of cytotoxic effects in terms of cell morphology and viability. We confirmed the feasibility of implanting and actuating our device within a sciatic nerve gap and observed axonal outgrowth following device implantation. The successful fabrication and implementation of our device provides a novel method for examining mechanical influences on nerve regeneration.

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Extreme Stretch Growth of Integrated Axons

Cited by 241 publications

References 28 publications

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Intracellular control of developmental and regenerative axon growth

A Novel Internal Fixator Device for Peripheral Nerve Regeneration

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