Axon Regeneration in Peripheral Nerves

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.306 ◽

2021 ◽

Author(s):

Arthur English

Keyword(s):

Nerve Injury ◽

Peripheral Nerves ◽

Axon Regeneration ◽

Axon Growth ◽

Injury Site ◽

Genetic Manipulations ◽

Novel Treatments ◽

The Central Nervous System ◽

Experimental Treatments ◽

Axonal Protein

Despite the intrinsically greater capacity for axons to regenerate in injured peripheral nerves than after injury to the central nervous system, functional recovery after most nerve injuries is very poor. A need for novel treatments that will enhance axon regeneration and improve recovery is substantial. Several such experimental treatments have been studied, each based on part of the stereotypical cellular responses that follow a nerve injury. Genetic manipulations of Schwann cells that have transformed from a myelinating to a repair phenotype that either increase their production of axon growth-promoting molecules, decrease production of inhibitors, or both result in enhanced regeneration. Local or systemic application of these molecules or small molecule mimetics of them also will promote regeneration. The success of treatments that stimulate axonal protein synthesis at the site of the nerve injury and in the growing axons, an early and important response to axon injury, is significant, as is that of manipulations of the types of immune cells that migrate into the injury site or peripheral ganglia. Modifications of the extracellular matrix through which the regenerating axons course, including the stimulation of new blood vessel formation, promotes the navigation of nascent regenerating neurites past the injury site, resulting in greater axon regeneration. Experimental induction of expression of regeneration associated gene activity in the cell bodies of the injured neurons is especially useful when regenerating axons must regenerate over long distances to reinnervate targets. The consistently most effective experimental approach to improving axon regeneration in peripheral nerves has been to increase the activity of the injured neurons, either through electrical, optical, or chemogenetic stimulation or through exercise. These activity-dependent experimental therapies show greatest promise for translation to use in patients.

Download Full-text

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

10.1101/259408 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ishwariya Venkatesh ◽

Vatsal Mehra ◽

Zimei Wang ◽

Ben Califf ◽

Murray G. Blackmore

Keyword(s):

Cortical Neurons ◽

Gene Networks ◽

Target Genes ◽

Axon Regeneration ◽

Axon Growth ◽

Chromatin Accessibility ◽

Integrated Analysis ◽

The Central Nervous System ◽

Pioneer Factors ◽

Growth Ability

ABSTRACTAxon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments.

Download Full-text

Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1509754112 ◽

2015 ◽

Vol 112 (49) ◽

pp. 15220-15225 ◽

Cited By ~ 15

Author(s):

Camille Brochier ◽

James I. Jones ◽

Dianna E. Willis ◽

Brett Langley

Keyword(s):

Molecular Mechanisms ◽

Axon Regeneration ◽

Neuronal Loss ◽

Axon Growth ◽

Axonal Growth ◽

Growth Inhibitory ◽

Physical Barriers ◽

The Central Nervous System ◽

Novel Target ◽

Inhibitory Molecules

Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.

Download Full-text

Intra-axonal translation of Khsrp mRNA slows axon regeneration by destabilizing localized mRNAs

10.1101/2020.10.26.356162 ◽

2020 ◽

Author(s):

Priyanka Patel ◽

Courtney Buchanan ◽

Amar N. Kar ◽

Seung Joon Lee ◽

Pabitra K. Sahoo ◽

...

Keyword(s):

Sciatic Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Rna Binding ◽

Axon Regeneration ◽

Axon Growth ◽

Mrna Translation ◽

Crush Injury ◽

Sciatic Nerve Crush ◽

Axonal Translation

ABSTRACTProteins generated by localized mRNA translation in axons support nerve regeneration through retrograde injury signaling and localized axon growth mechanisms. RNA binding proteins (RBP) are needed for this and other aspects of post-transcriptional control of localized mRNAs, but only a limited number of axonal RBPs have been reported. We used a targeted mass spectrometry approach to profile the axonal RBPs in naïve, injured and regenerating PNS axons. We detected 76 axonal proteins that are reported to have RNA binding activity, with the levels of several of these axonal RBPs changing with axonal injury and regeneration. These axonal RBPs with altered axoplasm levels include KHSRP that we previously reported decreases neurite outgrowth in developing CNS neurons. We show that KHSRP levels rapidly increase in sciatic nerve axons after crush injury and remain elevated increasing in levels out to 28 days post-sciatic nerve crush injury. Khsrp mRNA localizes into axons and the rapid increase in axonal KHSRP after axotomy is mediated by the local translation of its mRNA. KHSRP binds to mRNAs with a 3’UTR AU-rich element and targets those mRNAs to the cytoplasmic exosome for degradation. KHSRP knockout mice show increased axonal levels of defined KHSRP target mRNAs, Gap43 and Snap25 mRNAs, following sciatic nerve injury and accelerated nerve regeneration in vivo. These data indicate that axonal translation of Khsrp mRNA following nerve injury serves to destabilize other axonal mRNAs and slow axon regeneration.

Download Full-text

Evidence for a Blood Ganglion Barrier in the Superior Cervical Ganglion of the Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053681 ◽

1982 ◽

Vol 40 ◽

pp. 204-204

Author(s):

D. M. DePace

Keyword(s):

Blood Vessels ◽

Superior Cervical Ganglion ◽

Peripheral Nerves ◽

Time Schedule ◽

Transmission Electron ◽

Cervical Ganglion ◽

The Central Nervous System ◽

Cervical Ganglia ◽

Capillary Circulation ◽

And Control

The majority of blood vessels in the superior cervical ganglion possess a continuous endothelium with tight junctions. These same features have been associated with the blood brain barrier of the central nervous system and peripheral nerves. These vessels may perform a barrier function between the capillary circulation and the superior cervical ganglion. The permeability of the blood vessels in the superior cervical ganglion of the rat was tested by intravenous injection of horseradish peroxidase (HRP). Three experimental groups of four animals each were given intravenous HRP (Sigma Type II) in a dosage of.08 to.15 mg/gm body weight in.5 ml of.85% saline. The animals were sacrificed at five, ten or 15 minutes following administration of the tracer. Superior cervical ganglia were quickly removed and fixed by immersion in 2.5% glutaraldehyde in Sorenson's.1M phosphate buffer, pH 7.4. Three control animals received,5ml of saline without HRP. These were sacrificed on the same time schedule. Tissues from experimental and control animals were reacted for peroxidase activity and then processed for routine transmission electron microscopy.

Download Full-text

Cyr61 promotes Schwann cell proliferation and migration via αvβ3 integrin

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00360-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhenghui Cheng ◽

Yawen Zhang ◽

Yinchao Tian ◽

Yuhan Chen ◽

Fei Ding ◽

...

Keyword(s):

Nerve Injury ◽

Peripheral Nerves ◽

Molecular Mechanisms ◽

Αvβ3 Integrin ◽

Promoting Effect ◽

Ccn Family ◽

And Migration ◽

Proliferation And Migration

Abstract Background Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. Results We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvβ3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvβ3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. Conclusions In this study, we found that Cyr61 promotes SC proliferation and migration via αvβ3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC’s function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.

Download Full-text

Bioluminescent Optogenetics: A Novel Experimental Therapy to Promote Axon Regeneration after Peripheral Nerve Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22137217 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7217

Author(s):

Arthur W. English ◽

Ken Berglund ◽

Dario Carrasco ◽

Katharina Goebel ◽

Robert E. Gross ◽

...

Keyword(s):

Transgenic Mice ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Viral Vectors ◽

Axon Regeneration ◽

Intraperitoneal Administration ◽

Experimental Therapy ◽

Promising Therapeutic Approach ◽

Compound Muscle Action Potentials

Functional recovery after peripheral nerve injury (PNI) is poor, mainly due to the slow and incomplete regeneration of injured axons. Experimental therapies that increase the excitability of the injured axons have proven remarkably successful in promoting regeneration, but their clinical applicability has been limited. Bioluminescent optogenetics (BL-OG) uses luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels that could be used to increase neuronal excitability if exposed to a suitable substrate. Excitatory luminopsins were expressed in motoneurons of transgenic mice and in wildtype mice transduced with adeno-associated viral vectors. Intraperitoneal administration of coelenterazine (CTZ), a known luciferase substrate, generated intense bioluminescence in peripheral axons. This bioluminescence increased motoneuron excitability. A single administration of CTZ immediately after sciatic nerve transection and repair markedly enhanced motor axon regeneration. Compound muscle action potentials were 3–4 times larger than controls by 4 weeks after injury. The results observed with transgenic mice were comparable to those of mice in which the luminopsin was expressed using viral vectors. Significantly more motoneurons had successfully reinnervated muscle targets four weeks after nerve injury in BL-OG treated mice than in controls. Bioluminescent optogenetics is a promising therapeutic approach to enhancing axon regeneration after PNI.

Download Full-text

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽

10.3390/cells10051078 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1078

Author(s):

Debasish Roy ◽

Andrea Tedeschi

Keyword(s):

Nervous System ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

Axon Regeneration ◽

Axon Growth ◽

The Body ◽

Cns Repair ◽

Cord Injury ◽

Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

Download Full-text

Continuation of fast axonal transport in regenerating axons in vitro

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-189 ◽

1979 ◽

Vol 57 (11) ◽

pp. 1251-1255

Author(s):

M. A. Bisby ◽

C. E. Hilton

Keyword(s):

Sciatic Nerve ◽

Vagus Nerve ◽

Axonal Transport ◽

Nerve Injury ◽

Axon Regeneration ◽

Free Medium ◽

Fast Axonal Transport ◽

Sensory Axons

A previous study by McLean and co-workers reported that regenerating axons of the rabbit vagus nerve were unable to sustain axonal transport in vitro for several months after nerve injury. In contrast, we found that sensory axons of the rat sciatic nerve were able to transport 3H-labeled protein into their regenerating portions distal to the site of injury within a week after injury when placed in vitro. Transport in vitro was not significantly less than transport in axons maintained in vivo for the same period. Transport occurred in the medium that was used by the McLean group, but was significantly reduced in calcium-free medium. When axon regeneration was delared, only small amounts of activity were present in the nerve distal to the site of injury, showing that labeled protein normally present in that part of the nerve was associated with axons and was not a result of local precursor uptake by nonneural elements in the sciatic nerve. We were not able to explain the failure of McLean and co-workers to demonstrate transport in vitro in regenerating vagus nerve, but we conclude that there is no general peculiarity of growing axons that makes them unable to sustain transport in vitro.

Download Full-text