Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

Eddie, Chi Him; Ômura, Takao; Cobos, Enrique J.; Latrémolière, Alban; Ghasemlou, Nader; Brenner, Gary J.; Veen, J. Edward Van; Barrett, Lee; Sawada, Tomokazu; Gao, Fuying; Coppola, Giovanni; Gertler, Frank B.; Costigan, Michael; Geschwind, Dan; Woolf, Clifford J.

doi:10.1172/jci58675

Cited by 210 publications

(256 citation statements)

References 73 publications

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“…We investigated recovery of motoric functions—measuring the footbase angle of mice in single‐frame motion analysis (SFMA) (Figure 1c) as a highly reproducible marker for functional muscle reinnervation (Fey, Schachner, & Irintchev, 2010). Again, old mice showed significantly delayed recovery of motoric functions, also exhibiting recovery delay in ability to spread their toes (Figure 1d)—an alternative marker for motor reinnervation efficacy after peripheral nerve damage (Ma et al, 2011). Our tests indicated delayed but almost full functional recovery of old mice after peripheral nerve crush injury.…”

Section: Resultsmentioning

confidence: 92%

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Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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Section: Resultsmentioning

confidence: 92%

“…The description of single‐frame motion analysis (SFMA) can be found in Fey et al (2010), toe‐spread test was performed as previously described in Ma et al (2011) and Semmes–Weinstein monofilament test was conducted according to Bradman, Ferrini, Salio, and Merighi (2015). For details see Supporting Information Appendix S1.…”

Section: Methodsmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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“…Longitudinal cryosections (14 mm) of sciatic nerves were immunohistochemically stained with an antibody against the regeneration-associated protein SCG10 (Novus Biologicals, Cambridge, UK) 50 were quantified at 1, 1.5, 2, 2.5, 3, 3.5 mm beyond the carbon-labelled injury site, as described previously 3 . Statistical significances of intergroup differences were evaluated using a one-way ANOVA followed by the Holm-Sidak post-hoc test.…”

Section: Methodsmentioning

confidence: 99%

“…This successful regeneration is associated with significant, though often incomplete functional restoration 1,2 . Measures increasing the growth rate of regenerating axons reportedly improve the functional outcome after peripheral nerve lesion and are therefore from a clinical point of view desirable 3 .…”

mentioning

confidence: 99%

Sustained GSK3 activity markedly facilitates nerve regeneration

et al. 2014

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Promotion of axonal growth of injured DRG neurons improves the functional recovery associated with peripheral nerve regeneration. Both isoforms of glycogen synthase kinase 3 (GSK3; a and b) are phosphorylated and inactivated via phosphatidylinositide 3-kinase (PI3K)/AKT signalling upon sciatic nerve crush (SNC). However, the role of GSK3 phosphorylation in this context is highly controversial. Here we use knock-in mice expressing GSK3 isoforms resistant to inhibitory PI3K/AKT phosphorylation, and unexpectedly find markedly accelerated axon growth of DRG neurons in culture and in vivo after SNC compared with controls. Moreover, this enhanced regeneration strikingly accelerates functional recovery after SNC. These effects are GSK3 activity dependent and associated with elevated MAP1B phosphorylation. Altogether, our data suggest that PI3K/AKT-mediated inhibitory phosphorylation of GSK3 limits the regenerative outcome after peripheral nerve injury. Therefore, suppression of this internal 'regenerative break' may potentially provide a new perspective for the clinical treatment of nerve injuries.

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“…Among the up-regulated genes were a number that are also induced after sciatic nerve lesion (25) and have demonstrated roles in promoting axon regeneration in other systems (Dataset S3). These include small proline-rich repeat protein 1A (Sprr1a), fibroblast growth factor-inducible 14 (Fn14), and heat shock protein beta-1 (Hspb1) (26)(27)(28), as well as the transcription factors activating transcription factor 3 (ATF3) and Kruppel-like factor 6 (Klf6) (29,30). Gene ontology and pathway analysis of the most significantly down-regulated genes revealed enrichment for terms relevant for the maturation of neurons (Dataset S2), including Brn3a and Brn3b, which may reflect a broader pattern of RGC dedifferentiation that could enhance regenerative capacity (31).…”

Section: G K O and R)mentioning

confidence: 99%

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

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

281

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

Cited by 210 publications

References 73 publications

Inflammaging impairs peripheral nerve maintenance and regeneration

Inflammaging impairs peripheral nerve maintenance and regeneration

Sustained GSK3 activity markedly facilitates nerve regeneration

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

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