scholarly journals The Virtuous Cycle of Axon Growth: Axonal Transport of Growth‐Promoting Machinery as an Intrinsic Determinant of Axon Regeneration

2018 ◽  
Vol 78 (10) ◽  
pp. 898-925 ◽  
Author(s):  
Veselina Petrova ◽  
Richard Eva
Keyword(s):  
Axonal Transport ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Growth Promoting ◽  
Virtuous Cycle

scholarly journals Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hyo Rim Ko ◽  
Il-Sun Kwon ◽  
Inwoo Hwang ◽  
Eun-Ju Jin ◽  
Joo-Ho Shin ◽  
...  
Keyword(s):  
Growth Cone ◽  
Axonal Regeneration ◽  
Potential Role ◽  
Axon Regeneration ◽  
Hippocampal Slices ◽  
Axon Growth ◽  
Mechanistic Studies ◽  
Cone Formation ◽  
Growth Promoting ◽  
Inhibitor Of Dna Binding

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration.

Homing behaviour of regenerating axons in the amphibian limb

Development ◽  
1989 ◽  
Vol 106 (4) ◽  
pp. 707-715
Author(s):  
S. Wilson ◽  
D.A. Tonge ◽  
N. Holder
Keyword(s):  
Electron Microscopy ◽  
Horseradish Peroxidase ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Triturus Cristatus ◽  
Sequence Of Events ◽  
Growth Promoting ◽  
Directed Growth ◽  
Forearm Flexor ◽  
Over Time

Following peripheral nerve deviation in the limbs of urodele amphibians axons regrow distally toward their previous target muscles (Holder et al. 1984; Proc. Roy. Soc. Lond. B 222, 477–489). This study describes analysis of this axon regeneration over time following deviation of the forearm flexor nerve in Triturus cristatus and the extensor cranialis nerve in the axolotl. Using horseradish peroxidase (HRP) axonal tracing, electrophysiology and electron microscopy, we describe the sequence of events leading to reestablishment of functional innervation. HRP fills reveal axons leaving the deviated nerve via a number of possible routes and they invariably grow distally. Many axons take a path close to that of the original nerve but others fasciculate forming parallel paths. Electrophysiology and electron microscopy show that axons in the deviated region of the nerve degenerate extensively compared with cut, but undeviated, controls. The results are discussed in terms of the possible axon-growth-promoting mechanisms that result in directed growth.

scholarly journals Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

2018 ◽  
Author(s):  
Seung Joon Lee ◽  
Amar N. Kar ◽  
Matthew D. Zdradzinski ◽  
Priyanka Patel ◽  
Pabitra K. Sahoo ◽  
...  
Keyword(s):  
Axon Regeneration ◽  
Growth Promotion ◽  
Axon Growth ◽  
Alternatively Spliced ◽  
Selective Localization ◽  
Summary Statement ◽  
Growth Promoting ◽  
Axon Specification ◽  
Mrna Isoform

ABSTRACTThe small Rho-family GTPase Cdc42 has long been known to have a role in cell motility and axon growth. The eukaryotic CDC42 gene is alternatively spliced to generate mRNAs with two different 3’UTRs that encode proteins with distinct C-termini. The C-termini of these Cdc42 proteins include CAAX and CCAX motifs for post-translational prenylation and palmitoylation, respectively. Palmitoyl-Cdc42 protein was previously shown to contribute to dendrite maturation, while the prenyl-Cdc42 protein contributes to axon specification and its mRNA was detected in neurites. Here, we show that the mRNA encoding prenyl-Cdc42 isoform preferentially localizes into PNS axons and this localization selectively increases in vivo during PNS axon regeneration. Isoform specific siRNA knockdowns, rescue experiments with siRNA-resistant Cdc42 isoforms, and pharmacologically targeting Cdc42 activity indicate that prenyl-Cdc42 promotes axon growth while the palmitoyl-Cdc42 has little growth promoting activity. The growth promotion by prenyl-Cdc42 requires axonal mRNA localization with localized translation and an intact C-terminal CaaX motif for localized prenylation of the encoded protein. Together, these data show that alternative splicing of the CDC42 gene product generates an axon growth promoting locally synthesized prenyl-Cdc42 protein.SUMMARY STATEMENTAxon regeneration drives selective localization of alternatively spliced CDC42 isoform to PNS axons.

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.

Continuation of fast axonal transport in regenerating axons in vitro

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.

Axon Regeneration in Peripheral Nerves

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.

scholarly journals ­­STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

2020 ◽  
Author(s):  
xuezhi zhou ◽  
Yujue Wang ◽  
Manjuan Peng ◽  
Ye He ◽  
Jingjie Peng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Layer Thickness ◽  
Axonal Regeneration ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Müller Cells ◽  
Control Group ◽  
Marker Genes ◽  
Mrna Levels ◽  
Muller Cells

Abstract BackgroundMüller differentiated RGCs have potential therapeutic value for glaucoma. However, axonal regeneration of differentiated RGCs has been a difficult problem. Studies have confirmed that STAT3 and Y27632 play essential roles in regulating neuronal axon regeneration. Whether STAT3 and Y27632 can induce the Müller differentiated RGCs axon regeneration is still unknown.MethodRetina Müller cells were isolated and purified from Day 21 SD rats’ retina and were differentiated into retinal stem cells. The stem cells were randomly divided into five groups (control group, AAV-STAT3 group, shSTAT3 group, Y27632 group and AAV-STAT3 + Y27632 group). The axon length in each group were measured by ImageJ. Immunofluorescence were used to label the RGCs. The mRNA level of pluripotent associated and differentiation-associated proteins was analysed by qRT-PCR. Stem cells in different groups were injected into mice model of glaucoma. Immunohistochemical, Immunohistochemistry and OCT were performed to access RGC layer thickness in glaucoma model. VEP was used to detect the optic nerve conduction function.ResultsIn this study, we found that overexpression of STAT3 could promote the growth of RGCs axons generated by Müller cell differentiation. Combined with Y27632, axonal regeneration was significantly longer than that of the STAT3 group. However, after STAT3 was knocked out, axonal regeneration significantly decreased or even stopped. The mRNA levels of Esrrb, Prdm14, Sox2, and Rex1 in Müller differentiated RGCs after overexpression STAT3 combined with Y27632 were significantly increased, while the mRNA levels of Nestin, Eomes, Mixl1 and Gata4 were significantly decreased. The mRNA levels of Socs3, Pten, Klf9, and Mdm4 were significantly decreased, while the mRNA levels of Dclk2, Armcx1, C-MYC, and Nrn1 were significantly increased. The mRNA levels of differentiation and pluripotency marker genes showed opposite results after STAT3 deletion. After injecting Müller differentiated RGCs intervened by STAT3 combined with Y27632 into the eyes of the glaucoma model mice, the axon length, OCT displayed RGC layer thickness and the electrophysiology indicated by VEP were superior to those of the glaucoma model group.ConclusionsThese findings suggested that STAT3 combined with Y27632 can significantly improve the axonal growth level of RGCs, and reveal the potential mechanism to induce pluripotency of RGCs.

scholarly journals βII-spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport

2019 ◽  
Vol 116 (31) ◽  
pp. 15686-15695 ◽  
Author(s):  
Damaris N. Lorenzo ◽  
Alexandra Badea ◽  
Ruobo Zhou ◽  
Peter J. Mohler ◽  
Xiaowei Zhuang ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Plasma Membranes ◽  
Brain Connectivity ◽  
Axon Growth ◽  
Membrane Skeleton ◽  
Lipid Binding ◽  
Organelle Transport ◽  
Double Knockout ◽  
Micrometer Scale

βII-spectrin is the generally expressed member of the β-spectrin family of elongated polypeptides that form micrometer-scale networks associated with plasma membranes. We addressed in vivo functions of βII-spectrin in neurons by knockout of βII-spectrin in mouse neural progenitors. βII-spectrin deficiency caused severe defects in long-range axonal connectivity and axonal degeneration. βII-spectrin–null neurons exhibited reduced axon growth, loss of actin–spectrin-based periodic membrane skeleton, and impaired bidirectional axonal transport of synaptic cargo. We found that βII-spectrin associates with KIF3A, KIF5B, KIF1A, and dynactin, implicating spectrin in the coupling of motors and synaptic cargo. βII-spectrin required phosphoinositide lipid binding to promote axonal transport and restore axon growth. Knockout of ankyrin-B (AnkB), a βII-spectrin partner, primarily impaired retrograde organelle transport, while double knockout of βII-spectrin and AnkB nearly eliminated transport. Thus, βII-spectrin promotes both axon growth and axon stability through establishing the actin–spectrin-based membrane-associated periodic skeleton as well as enabling axonal transport of synaptic cargo.

scholarly journals B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

2014 ◽  
Vol 211 (5) ◽  
pp. 801-814 ◽  
Author(s):  
Kevin J. O’Donovan ◽  
Kaijie Ma ◽  
Hengchang Guo ◽  
Chen Wang ◽  
Fang Sun ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Loss Of Function ◽  
Pten Loss ◽  
Raf Kinase ◽  
Central Nervous Systems ◽  
Neurotrophin Signaling ◽  
Peripheral Sensory

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

scholarly journals Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy.

1986 ◽  
Vol 103 (5) ◽  
pp. 1921-1931 ◽  
Author(s):  
D J Goldberg ◽  
D W Burmeister
Keyword(s):  
Axonal Transport ◽  
Growth Cone ◽  
Axon Growth ◽  
Leading Edge ◽  
Main Body ◽  
Differential Interference Contrast ◽  
Differential Interference Contrast Microscopy ◽  
Fast Axonal Transport ◽  
Contrast Microscopy ◽  
Interference Contrast Microscopy

The regenerative growth in culture of the axons of two giant identified neurons from the central nervous system of Aplysia californica was observed using video-enhanced contrast-differential interference contrast microscopy. This technique allowed the visualization in living cells of the membranous organelles of the growth cone. Elongation of axonal branches always occurred through the same sequence of events: A flat organelle-free veil protruded from the front of the growth cone, gradually filled with vesicles that entered by fast axonal transport and Brownian motion from the main body of the growth cone, became more voluminous and engorged with organelles (vesicles, mitochondria, and one or two large, irregular, refractile bodies), and, finally, assumed the cylindrical shape of the axon branch with the organelles predominantly moving by bidirectional fast axonal transport. The veil is thus the nascent axon. Because veils appear to be initially free of membranous organelles, addition of membrane to the plasmalemma by exocytosis is likely to occur in the main body of the growth cone rather than at the leading edge. Veils almost always formed with filopodial borders, protruding between either fully extended or growing filopodia. Therefore, one function of the filopodia is to direct elongation by demarcating the pathway along which axolemma flows. Models of axon growth in which the body of the growth cone is pulled forward, or in which advance of the leading edge is achieved by filopodial shortening or contraction against an adhesion to the substrate, are inconsistent with our observations. We suggest that, during the elongation phase of growth, filopodia may act as structural supports.

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