Nerve regeneration in the peripheral and central nervous systems

Gordon, Tessa

doi:10.1113/jp270898

Cited by 39 publications

(34 citation statements)

References 48 publications

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“…Growth of developing axons requires a process of polarized axonal extension, which stops once axons reach their targets and establish new connections. This growth ability at embryonic stages is progressively lost in adulthood, but can be revived by peripheral neurons upon injury [1][2][3]5]. Indeed, axonal growth also occurs during regeneration of adult peripheral axons, with some differences: regenerating axons need to form growth cones starting from the severed stumps that can be far away from the cell bodies, and often need to cover long distances, with high demand of building materials and transport.…”

Section: Central Vs Peripheral Axonal Regenerationmentioning

confidence: 99%

“…Indeed spinal cord injuries, traumatic brain injuries, stroke, and various neurological disorders typically result in regeneration failure, with poor prognosis for patients. The differences in regeneration capabilities between peripheral and central neurons rely on both intrinsic qualities of the neurons themselves, and on the neuronal environment, mainly glial-driven, which impacts the regenerative outcome [1][2][3][4][5][6][17][18][19]. The finding that some injured CNS neurons are able to re-grow into grafted permissive substrates has paved the way for the identification of inhibitory factors associated with glial scars, myelin debris, etc.…”

Section: Central Vs Peripheral Axonal Regenerationmentioning

confidence: 99%

“…The peripheral nervous system (PNS) can regenerate following injury, at variance from the central nervous system (CNS) [1][2][3][4][5][6]. Indeed, enabling axon regeneration after CNS injury remains a major challenge in neurobiology [1].…”

Section: Introductionmentioning

confidence: 99%

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Signals Orchestrating Peripheral Nerve Repair

Rigoni

Negro

2020

Cells

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The peripheral nervous system has retained through evolution the capacity to repair and regenerate after assault from a variety of physical, chemical, or biological pathogens. Regeneration relies on the intrinsic abilities of peripheral neurons and on a permissive environment, and it is driven by an intense interplay among neurons, the glia, muscles, the basal lamina, and the immune system. Indeed, extrinsic signals from the milieu of the injury site superimpose on genetic and epigenetic mechanisms to modulate cell intrinsic programs. Here, we will review the main intrinsic and extrinsic mechanisms allowing severed peripheral axons to re-grow, and discuss some alarm mediators and pro-regenerative molecules and pathways involved in the process, highlighting the role of Schwann cells as central hubs coordinating multiple signals. A particular focus will be provided on regeneration at the neuromuscular junction, an ideal model system whose manipulation can contribute to the identification of crucial mediators of nerve re-growth. A brief overview on regeneration at sensory terminals is also included.

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Section: Central Vs Peripheral Axonal Regenerationmentioning

confidence: 99%

Section: Central Vs Peripheral Axonal Regenerationmentioning

confidence: 99%

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Signals Orchestrating Peripheral Nerve Repair

Rigoni

Negro

2020

Cells

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“…Schwann cells represent the glial component of the peripheral nervous system. As well as supporting axonal function in a physiological status, they play a critical role during the degenerative and the regenerative processes activated after nerve injury (Namgung, 2014 ; Gordon, 2016 ; Jessen and Mirsky, 2016 ). A severe damage to the nerve tissue determines the loss of axon-Schwann cell contact with subsequent change in Schwann cell phenotype.…”

Section: Introductionmentioning

confidence: 99%

Soluble Neuregulin1 Down-Regulates Myelination Genes in Schwann Cells

Soury

Fornasari

Morano

et al. 2018

Front. Mol. Neurosci.

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Peripheral nerves are characterised by the ability to regenerate after injury. Schwann cell activity is fundamental for all steps of peripheral nerve regeneration: immediately after injury they de-differentiate, remove myelin debris, proliferate and repopulate the injured nerve. Soluble Neuregulin1 (NRG1) is a growth factor that is strongly up-regulated and released by Schwann cells immediately after nerve injury. To identify the genes regulated in Schwann cells by soluble NRG1, we performed deep RNA sequencing to generate a transcriptome database and identify all the genes regulated following 6 h stimulation of primary adult rat Schwann cells with soluble recombinant NRG1. Interestingly, the gene ontology analysis of the transcriptome reveals that NRG1 regulates genes belonging to categories that are regulated in the peripheral nerve immediately after an injury. In particular, NRG1 strongly inhibits the expression of genes involved in myelination and in glial cell differentiation, suggesting that NRG1 might be involved in the de-differentiation (or “trans-differentiation”) process of Schwann cells from a myelinating to a repair phenotype. Moreover, NRG1 inhibits genes involved in the apoptotic process, and up-regulates genes positively regulating the ribosomal RNA processing, thus suggesting that NRG1 might promote cell survival and stimulate new protein expression. This in vitro transcriptome analysis demonstrates that in Schwann cells NRG1 drives the expression of several genes which partially overlap with genes regulated in vivo after peripheral nerve injury, underlying the pivotal role of NRG1 in the first steps of the nerve regeneration process.

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“…Following neuronal injury, DLK activation and up-regulation is responsible for the retrograde transport of stress signals to the nucleus, resulting in changes in the activities of transcription factors like JUN and signal transducer and activator of transcription three (STAT3) ( 11 , 12 ). In the PNS, the resulting gene expression changes promote axon regeneration and, in some cases, the restoration of function ( 13 , 14 ). In contrast, in the less regeneration-permissive environment of the CNS, DLK-dependent alterations in gene expression often culminate in cell death.…”

mentioning

confidence: 99%

Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons

Patel

Broyer

Lee

et al. 2020

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

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Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases.

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Nerve regeneration in the peripheral and central nervous systems

Cited by 39 publications

References 48 publications

Signals Orchestrating Peripheral Nerve Repair

Signals Orchestrating Peripheral Nerve Repair

Soluble Neuregulin1 Down-Regulates Myelination Genes in Schwann Cells

Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons

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