c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration

Arthur‐Farraj, Peter; Latouche, Morwena; Wilton, Daniel K.; Quintes, Susanne; Chabrol, E; Banerjee, Annbily; Woodhoo, Ashwin; Jenkins, B; Rahman, Mary; Turmaine, Mark; Wicher, Grzegorz; Mitter, Richard; Greensmith, Linda; Behrens, Axel; Raivich, Gennadij; Mirsky, Rhona; Jessen, Kristján R.

doi:10.1016/j.neuron.2012.06.021

Cited by 696 publications

(968 citation statements)

References 38 publications

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“…To better understand the reasons for diminished myelination in aged peripheral nerves, we screened for alterations of intrinsic Schwann cell repair pathways such as the Ras/Raf/ERK and the cJun (Arthur‐Farraj et al, 2012; Harrisingh et al, 2004; Napoli et al, 2012) in intact sciatic nerves. Immunoblot analysis (Figure 5c, d) revealed no changes of p75 or Erk1/2 protein expression, but Erk1/2 protein appeared more phosphorylated in old animals.…”

Section: Resultsmentioning

confidence: 99%

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: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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“…Upon injury, these genes are derepressed by H3K27 demethylation and activated by H3K4 methylation at promoter regions and by H3K27 acetylation at enhancers, the latter correlating with recruitment of the transcription factor cJun [52 ,53], a major inducer of SC conversion into repair cells [54]. This mechanism allows the expression of injury-induced genes including Shh and the neurotrophic factor Gdnf [52 ], and thus promotes axonal regrowth after lesion.…”

Section: Hats Hdacs Hmts and Hdms Control The Conversion Into Repaimentioning

confidence: 99%

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

Jacob

2017

Current Opinion in Neurobiology

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Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment. AddressDepartment of Biology, University of Fribourg, Chemin du Musé e 10, 1700 Fribourg, SwitzerlandCorresponding author: Jacob, Claire (claire.jacob@unifr.ch) IntroductionSCs originate from neural crest cells that also give rise to other cell types including sensory neurons, chondrocytes, melanocytes, smooth-muscle cells [1,2]. After specification in SC precursors, the lineage further differentiates into immature SCs that encircle bundles of axons of different calibers. Next, big caliber axons are sorted in a one-to-one relationship with SCs by a process called radial sorting which leads to the promyelinating stage. The last step of maturation is the myelination process where SCs build a thick myelin sheath rich in lipids around axons (Figure 1). Meanwhile, small caliber axons remain in bundles associated with non-myelinating SCs and persist as Remak bundles in adult nerves [3,4]. Myelin provides axonal insulation and fast conduction of electric signals along axons; its formation and maintenance are thus critical for neuronal functions. By contrast, myelin is detrimental for axonal regrowth after lesion, because it contains growth inhibitory proteins [5]. However, SCs react quickly to an axonal lesion by dedifferentiating, digesting their own myelin -a process called myelinophagy [6] -and converting into repair cells [7,8] that foster axonal regrowth and guide axons back to their former target [9,10]. SCs then remyelinate regenerated axons (Figure 2). This remarkable SC plasticity allows the PNS to functionally regenerate after lesion.This review is focused on the mechanisms of SC development, maintenance and plasticity after lesion controlled by chromatin-remodeling enzymes. Chromatin remodeling regulates the accessibility of genes for the transcriptional machinery, and thereby gene activation and repression. Changes of chromatin architecture are controlled by ATP-dependent nucleosome remodeling and by covalent modifications, either on DNA by methylation or on histones by various post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation. Although our knowledge on these mechanisms is still very sparse, recent findings on the functions of chromatinremodeling enzymes have significantly contributed to a better understanding of their critical fu...

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“…If c-Jun is not induced, there is a dysfunction of repair of the cell and with subsequent failure of functional recovery as well as induction of neuronal death. Thus, this single glial transcription factor appears to be of extreme importance in this context (Arthur-Farraj et al, 2012). The c-Jun is also a negative regulator of the myelination (Parkinson et al, 2008).…”

Section: The Intrinsic Response In Neurons and Schwann Cells After Inmentioning

confidence: 99%

“…Therefore, the myelination of the outgrowing axons may be severely impaired. c-Jun is probably critical in this context, since it reprograms Schwann cells to generate a repair process in the cells after nerve injury (Arthur-Farraj, et al, 2012). In addition, the expression of trophic factors and adhesion molecules is determined by c-Jun.…”

Section: If a Nerve Injury Is Not Repaired Within Three Or Six Monthsmentioning

confidence: 99%

The Role of Timing in Nerve Reconstruction

Dahlin

2013

International Review of Neurobiology

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The surgeon, who treats nerve injuries, should have knowledge about how peripheral nerves react to trauma, particularly an understanding about the extensive pathophysiological alterations that occur both in the peripheral and in the central nervous system. A large number of factors influence the functional outcome, where the surgeon only can affect a few of them.In view of the new knowledge about the delicate intracellular signaling pathways that are rapidly initiated in neurons and in non-neuronal cells with the purpose to induce nerve regeneration, the timing of nerve repair and reconstruction after injury has gained more interest. It is crucial to understand and to utilize the inborn mechanisms for survival and regeneration of neurons and for activation, survival and proliferation of the Schwann cells and other cells that are acting after a nerve injury. Thus, experimental and clinical data clearly point towards the advantage of early nerve repair and reconstruction of injuries. Following an appropriate diagnosis of a nerve injury, the nerve should be promptly repaired or reconstructed, and new rehabilitation strategies should early be initiated. Considering nerve transfers in the treatment arsenal can shorten the time of nerve reinnervation of muscle targets. Timing of nerve repair and reconstruction is crucial after nerve injury.

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c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration

Cited by 696 publications

References 38 publications

Inflammaging impairs peripheral nerve maintenance and regeneration

Inflammaging impairs peripheral nerve maintenance and regeneration

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

The Role of Timing in Nerve Reconstruction

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