scholarly journals Inhibition of PTEN activity promotes IB4-positive sensory neuronal axon growth

2020 ◽  
Author(s):  
Li-Yu Zhou ◽  
Feng Han ◽  
Shi-Bin Qi ◽  
Jin-Jin Ma ◽  
Yan-Xia Ma ◽  
...  
Keyword(s):  
Nervous System ◽  
Sensory Neurons ◽  
Strong Evidence ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Clinical Problem ◽  
Sensory Axon ◽  
Nerve Injuries ◽  
Critical Process ◽  
Common Clinical Problem

AbstractTraumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduce total PTEN expression in adult sensory neurons, however, it did not alter the expression level of PTEN in IB4-positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4-positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4-positive neurons.

scholarly journals N6-methyladenine DNA demethylase ALKBH1 regulates mammalian axon regeneration

2020 ◽  
Author(s):  
Qiao Li ◽  
Cheng Qian ◽  
Harry Feng ◽  
Tyger Lin ◽  
Ying Huang ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Neuronal Development ◽  
Axon Regeneration ◽  
Physiological Function ◽  
Axon Growth ◽  
Epigenetic Mechanism ◽  
Sensory Axon ◽  
Functional Roles

AbstractRecent studies have shown that DNA N6-methyladenine (N6-mA) modification is emerging to be a novel and important epigenetic regulator of mammalian gene transcription. Several studies demonstrated DNA N6-mA in human or rodents was regulated by methyltransferase N6AMT1 and demethylase ALKBH1. Moreover, studies in mouse brain or human glioblastoma cells showed that reduced level of N6-mA or higher level of ALKBH1 was correlated with up regulated levels of genes associated with neuronal development. We thus investigated the functional roles of ALKBH1 in sensory axon regeneration. Our results showed that ALKBH1 regulated the level of N6-mA in sensory neurons, and upon peripheral nerve injury ALKBH1 was up regulated in mouse sensory neurons. Functionally, knocking down ALKBH1 in sensory neurons resulted in reduced axon regeneration in vitro and in vivo, which could be rescued by simultaneously knocking down N6AMT1. Moreover, knocking down ALKBH1 led to decreased levels of many neurodevelopment regulatory genes, including neuritin that is well known to enhance axon growth and regeneration. Our study not only revealed a novel physiological function of DNA N6-mA, but also identified a new epigenetic mechanism regulating mammalian axon regeneration.Significance StatementThe study demonstrated that DNA N6-methyladenine (N6-mA) modification played important roles in regulation of sensory axon regeneration, likely through controlling the expression of neurodevelopmental associated genes. The results will add new evidence about the physiological function of DNA N6-mA and its regulatory demethylase ALKBH1 in neurons.

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

Cells ◽  
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.

Sensory activity affects sensory axon development in C. elegans

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1891-1902 ◽  
Author(s):  
E.L. Peckol ◽  
J.A. Zallen ◽  
J.C. Yarrow ◽  
C.I. Bargmann
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Sensory Deprivation ◽  
Axon Growth ◽  
System Structure ◽  
Sensory Axon ◽  
C Elegans ◽  
Sensory Axons ◽  
Axon Development ◽  
Sensory Activity

The simple nervous system of the nematode C. elegans consists of 302 neurons with highly reproducible morphologies, suggesting a hard-wired program of axon guidance. Surprisingly, we show here that sensory activity shapes sensory axon morphology in C. elegans. A class of mutants with deformed sensory cilia at their dendrite endings have extra axon branches, suggesting that sensory deprivation disrupts axon outgrowth. Mutations that alter calcium channels or membrane potential cause similar defects. Cell-specific perturbations of sensory activity can cause cell-autonomous changes in axon morphology. Although the sensory axons initially reach their targets in the embryo, the mutations that alter sensory activity cause extra axon growth late in development. Thus, perturbations of activity affect the maintenance of sensory axon morphology after an initial pattern of innervation is established. This system provides a genetically tractable model for identifying molecular mechanisms linking neuronal activity to nervous system structure.

scholarly journals Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

2021 ◽  
Author(s):  
Menghon Cheah ◽  
Yuyan Cheng ◽  
Veselina Petrova ◽  
Anda Cimpean ◽  
Pavla Jendelova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sensory Neurons ◽  
Axonal Regeneration ◽  
Dorsal Root ◽  
Axon Regeneration ◽  
Peripheral Nerve Regeneration ◽  
Axon Growth ◽  
Drg Neurons ◽  
Cns Regeneration ◽  
Sensory Axons

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1(α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration and caused expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum, trafficking, and signalling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPS-derived sensory neurons, validating their causal contributions. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, Tfeb, Yy1. Signalling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with a distinctive program that differs from that involved in PNS regeneration.

scholarly journals Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

2012 ◽  
Vol 32 (21) ◽  
pp. 7325-7335 ◽  
Author(s):  
C. L. Tan ◽  
M. R. Andrews ◽  
J. C. F. Kwok ◽  
T. G. P. Heintz ◽  
L. F. Gumy ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chondroitin Sulfate Proteoglycans ◽  
Sensory Axon

scholarly journals Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Transection is Driven by Cellular Intravitreal Sciatic Nerve Grafts

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1335
Author(s):  
Zubair Ahmed ◽  
Ellen L. Suggate ◽  
Ann Logan ◽  
Martin Berry
Keyword(s):  
Nervous System ◽  
Optic Nerve ◽  
Sciatic Nerve ◽  
Schwann Cells ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Retinal Ganglion ◽  
Nerve Transection ◽  
Nerve Grafts ◽  
Growth Inhibitory

Neurotrophic factors (NTF) secreted by Schwann cells in a sciatic nerve (SN) graft promote retinal ganglion cell (RGC) axon regeneration after either transplantation into the vitreous body of the eye or anastomosis to the distal stump of a transected optic nerve. In this study, we investigated the neuroprotective and growth stimulatory properties of SN grafts in which Schwann cells had been killed (acellular SN grafts, ASN) or remained intact (cellular SN grafts, CSN). We report that both intravitreal (ivit) implanted and optic nerve anastomosed CSN promote RGC survival and when simultaneously placed in both sites, they exert additive RGC neuroprotection. CSN and ASN were rich in myelin-associated glycoprotein (MAG) and axon growth-inhibitory ligand common to both the central nervous system (CNS) and peripheral nervous system (PNS) myelin. The penetration of the few RGC axons regenerating into an ASN at an optic nerve transection (ONT) site is limited into the proximal perilesion area, but is increased >2-fold after ivit CSN implantation and increased 5-fold into a CSN optic nerve graft after ivit CSN implantation, potentiated by growth disinhibition through the regulated intramembranous proteolysis (RIP) of p75NTR (the signalling trans-membrane moiety of the nogo-66 trimeric receptor that binds MAG and associated suppression of RhoGTP). Mϋller cells/astrocytes become reactive after all treatments and maximally after simultaneous ivit and optic nerve CSN/ASN grafting. We conclude that simultaneous ivit CSN plus optic nerve CSN support promotes significant RGC survival and axon regeneration into CSN optic nerve grafts, despite being rich in axon growth inhibitory molecules. RGC axon regeneration is probably facilitated through RIP of p75NTR, which blinds axons to myelin-derived axon growth-inhibitory ligands present in optic nerve grafts.

scholarly journals Calcium/calmodulin-dependent protein kinase II regulates mammalian axon growth by affecting F-actin length in growth cone

2019 ◽  
Author(s):  
Feng Xi ◽  
Ren-Jie Xu ◽  
Jin-Hui Xu ◽  
Wei-Hua Wang ◽  
Jin-Jin Ma ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Kinase ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Cytoskeletal Proteins ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
The Status ◽  
Dependent Protein ◽  
Regulatory Effects

AbstractWhile axon regeneration is a key determinant of functional recovery of the nervous system after injury, it is often poor in the mature nervous system. Influx of extracellular calcium (Ca2+) is one of the first phenomena that occur following axonal injury, and calcium/calmodulin-dependent protein kinase (CaMKII), a target protein for calcium ions, regulates the status of cytoskeletal proteins such as F-actin. Herein, we found that peripheral axotomy activates CaMKII in dorsal root ganglion (DRG) sensory neurons, and inhibition of CaMKII impairs axon growth in both the peripheral and central nervous systems (PNS and CNS, respectively). Most importantly, we also found that activation of CaMKII promotes PNS and CNS axon growth, and regulatory effects of CaMKII on axon growth occur via affecting the length of the F-actin. Thus, we believe our findings provide clear evidence that CaMKII is a critical modulator of mammalian axon regeneration.

scholarly journals Updates and challenges of axon regeneration in the mammalian central nervous system

2020 ◽  
Author(s):  
Cheng Qian ◽  
Feng-Quan Zhou
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Research Progress ◽  
Regeneration Ability ◽  
Long Distance ◽  
Mammalian Central Nervous System ◽  
Cord Injury

Abstract Axon regeneration in the mammalian central nervous system (CNS) has been a long-standing and highly challenging issue. Successful CNS axon regeneration will benefit many human diseases involving axonal damage, such as spinal cord injury, traumatic brain injury, glaucoma, and neurodegenerative diseases. The current consensus is that the diminished intrinsic regenerative ability in mature CNS neurons and the presence of extrinsic inhibitors blocking axon regrowth are two major barriers for axon regeneration. During the past decade, studies targeting the intrinsic axon growth ability via regulation of gene transcription have produced very promising results in optic nerve and/or spinal cord regeneration. Manipulations of various signaling pathways or the nuclear transcription factors directly have been shown to sufficiently drive CNS axon regrowth. Converging evidence reveals that some pro-regenerative transcriptomic states, which are commonly accomplished by more comprehensive epigenetic regulations, exist to orchestrate the complex tasks of injury sensing and axon regeneration. Moreover, genetic reprogramming achieved via transcriptome and epigenome modifications provides novel mechanisms for enhancing axon regeneration. Recent studies also highlighted the important roles of remodeling neuronal cytoskeleton in overcoming the extrinsic inhibitory cues. However, our knowledge about the cellular and molecular mechanisms by which neurons regulate their intrinsic axon regeneration ability and response to extrinsic inhibitory cues is still fragmented. Here, we provide an update about recent research progress in axon regeneration and discuss major remaining challenges for long-distance axon regeneration and the subsequent functional recovery.

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