Stretch growth of integrated axon tracts: Extremes and exploitations
Introduction
There is an almost secret form of axonal growth that has been hiding in plain sight, yet it is perhaps the most remarkable growth mechanism of all: extending axons at rates thought to be impossible. The process of ‘stretch growth of integrated axon tracts’ is in marked contrast to well-studied forms of axon growth, such as sprouting and regeneration, since it does not require chemical cues, physical guides, or even growth cones. Rather, for axons that have already formed synapses, rapid growth can be triggered solely by mechanical forces, as first proposed by Weiss (1941) (Fig. 1A). This process can be observed throughout nature, where the growth of animals supplies continuous mechanical tension on nerves and white matter tracts.
Stretch growth of integrated axons likely begins during embryogenesis after axons have sprouted from the cell body and traveled relatively short distances to synapse with their target cells. As the animal's body grows, the distance between most neuronal somata and target cells increases, thereby exerting tensile forces on the axons. Presumably, these forces stimulate the axons to add cytoskeleton, axolemma, and other cellular building materials somewhere along their central length to minimize strain. Otherwise, the axons would be stretched to the point of rupture. Since this general process has only just recently been demonstrated experimentally, many mysteries remain regarding how and where axon tracts can achieve such extreme rates of growth. Nonetheless, stretch growth of integrated axon tracts is currently being exploited as a promising new approach to repair the nervous system.
Section snippets
The extremes of stretch growth of integrated axon tracts in nature
One of the most extreme examples of axon stretch growth can be inferred from blue whale spinal cord development (Fig. 1B). As the size of the whale vertebrae grow in length, spinal axons are presumably placed under continuous mechanical tension. These integrated axons have no growth cones, but nonetheless undergo enormous growth, reaching an unimaginable 30 m for some tracts.1
Limited historic notice of stretch growth of integrated axon tracts
Perhaps one reason that stretch growth of axon tracts has not been well studied is the lack of an identifiable pathology linked with its disruption. Defects in the axonal stretch growth mechanism would likely be uniformly lethal very early in embryogenesis, leaving little evidence to attract attention. Nonetheless, the general concept of axon stretch growth has not been completely ignored. A paper from Paul Weiss appeared in a publication of a symposium on growth in 1941, in which he primarily
Experimental evidence of mechanical influences on axon sprouting
Based on experimental evidence, two distinct phases of mechanically induced axon growth are emerging, with the first occurring during axon sprouting. Although it has been well characterized that axon growth cones extending out from the neuron body are directionally guided by chemotaxic and haptotaxic cues (Dickson, 2002, Tessier-Lavigne and Goodman, 1996, Yu and Bargmann, 2001), the actual growth of the axon also appears to be dependent on mechanical stimuli. In pioneering studies first
Experimental evidence of extreme stretch growth of integrated axon tracts
The second phase of mechanically induced axon growth – elongation of integrated axon tracts – was not experimentally demonstrated until 2001, notably 60 years after Paul Weiss first suggested that this process occurs naturally during development. In vitro studies in our laboratory confirmed that integrated axon tracts spanning two populations of mammalian neurons could undergo stretch growth even at seemingly impossibly extreme rates, and maintained at these rates for at least several weeks in
The paradox of brain morphogenesis and stretch growth of axon tracts
The collective in vitro data demonstrate the natural phenomenon of long-term stretch growth of integrated axon tracts. Clearly, this process can occur at rates that defy our current understanding of axon growth. The experimental mechanical stretch of axon tracts is likely akin to natural developmental growth where relatively supple nervous tissue spanning growing rigid bony structures must either grow in kind or fail, as Weiss postulated. However, there is one very notable exception to this
Exploiting stretch growth of integrated axon tracts to repair the nervous system
Understanding the mechanisms of axon regeneration and guidance has been one of the top priorities in the field of neuroscience. Indeed, the primary strategy to repair the damaged spinal cord and other nerve injuries is to bridge the lesions by promoting axon regeneration. However, coaxing a sufficient number of axons to grow substantial distances has posed a significant challenge. This is particularly exemplified in human spinal cord injury, where lesions commonly extend several centimeters in
Conclusion
Ultimately, it is no longer a stretch to suggest that tension can actually be good for your nerves. Yet, there remain many secrets as to how the blue whale, or any large animal, can expand its nervous system so rapidly during development. It is certain that many as yet unidentified processes must occur to accomplish such unprecedented growth. It is anticipated that an enhanced understanding of mechanisms governing the important natural process of stretch growth of integrated axons will reveal
Acknowledgements
I would like to express my deep appreciation to the following colleagues who helped make this work possible: David F. Meaney, John A. Wolf, Bryan J. Pfister, Akira Iwata, Kevin D. Browne, Jason Huang, D. Kacy Cullen, Niranjan Kameswaran, and Jun Zhang.
This work was supported by the Sharpe Trust, as well as the following NIH grants: NS048949, NS38104, and NS056202.
References (37)
- et al.
Internodes can nearly double in length with gradual elongation of the adult rat sciatic nerve
J. Orthop. Res.
(2004) - et al.
Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype with a critique of slow transport theory
Prog. Neurobiol.
(2000) Axonal growth in response to experimentally applied mechanical tension
Dev. Biol.
(1984)- et al.
Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target
Cell
(2002) - et al.
What is slow axonal transport?
Exp. Cell Res.
(2008) The slow axonal transport debate
Trends Cell Biol.
(1998)The slow axonal transport of cytoskeletal proteins
Curr. Opin. Cell Biol.
(1998)- et al.
A physical model of axonal elongation: force, viscosity, and adhesions govern the mode of outgrowth
Biophys. J.
(2008) - et al.
Stretch-grown axons retain the ability to transmit active electrical signals
FEBS Lett.
(2006) - et al.
Development of transplantable nervous tissue constructs comprised of stretch-grown axons
J. Neurosci. Methods
(2006)
Slow axonal transport: fast motors in the slow lane
Curr. Opin. Cell Biol.
Slow axonal transport: stop and go traffic in the axon
Nat. Rev. Mol. Cell Biol.
Axonal transport of membranous and nonmembranous cargoes: a unified perspective
J. Cell Biol.
Pathophysiology of peripheral nerve injury: a brief review
Neurosurg. Focus
Kinetics of proliferation of cancer cells in neoplastic effusions in man
Cancer
Molecular mechanisms of axon guidance
Science
Peripheral nerve injury: a review and approach to tissue engineered constructs
Anat. Rec.
Intracellular transport in neurons
Physiol. Rev.
Cited by (121)
Spatial confinement: A spur for axonal growth
2023, Seminars in Cell and Developmental BiologyTraumatic brain injury recapitulates developmental changes of axons
2022, Progress in NeurobiologyComputational models of cortical folding: A review of common approaches
2022, Journal of BiomechanicsHuman photoreceptors switch from autonomous axon extension to cell-mediated process pulling during synaptic marker redistribution
2022, Cell ReportsCitation Excerpt :Interestingly, we found that even PRs incapable of cell-autonomous axon extension were able to extend axons when pulled by a motile non-PR cell (Figure 3). Previous work has shown that axons can be stretched to great lengths by experimental manipulation (Smith, 2009), and axons clearly lengthen because of body growth (Bremer and Granato, 2016; Miller and Suter, 2018). However, to our knowledge, this is the first report showing that direct cell-cell interactions can be responsible for axon lengthening.
Magnetically-actuated microposts stimulate axon growth
2022, Biophysical JournalA closed-loop multi-scale model for intrinsic frequency-dependent regulation of axonal growth
2022, Mathematical BiosciencesCitation Excerpt :In the second stage, the axon tip approaches its targets and synapses ultimately form [1,2]. The growth rate during this second stage depends on factors released by the target cells [3,4]. What determines the growth rate during the first stage?