scholarly journals Kinesin-1–powered microtubule sliding initiates axonal regeneration in Drosophila cultured neurons

2015 ◽  
Vol 26 (7) ◽  
pp. 1296-1307 ◽  
Author(s):  
Wen Lu ◽  
Margot Lakonishok ◽  
Vladimir I. Gelfand
Keyword(s):  
Neurite Outgrowth ◽  
Axonal Regeneration ◽  
Spinal Cord Injuries ◽  
Practical Importance ◽  
Subsequent Formation ◽  
Injury Site ◽  
Cytoskeleton Reorganization ◽  
Mixed Polarity ◽  
Mature Neurons ◽  
Conventional Kinesin

Understanding the mechanism underlying axon regeneration is of great practical importance for developing therapeutic treatment for traumatic brain and spinal cord injuries. Dramatic cytoskeleton reorganization occurs at the injury site, and microtubules have been implicated in the regeneration process. Previously we demonstrated that microtubule sliding by conventional kinesin (kinesin-1) is required for initiation of neurite outgrowth in Drosophila embryonic neurons and that sliding is developmentally down-regulated when neurite outgrowth is completed. Here we report that mechanical axotomy of Drosophila neurons in culture triggers axonal regeneration and regrowth. Regenerating neurons contain actively sliding microtubules; this sliding, like sliding during initial neurite outgrowth, is driven by kinesin-1 and is required for axonal regeneration. The injury induces a fast spike of calcium, depolymerization of microtubules near the injury site, and subsequent formation of local new microtubule arrays with mixed polarity. These events are required for reactivation of microtubule sliding at the initial stages of regeneration. Furthermore, the c-Jun N-terminal kinase pathway promotes regeneration by enhancing microtubule sliding in injured mature neurons.

scholarly journals Myelin basic protein enhances axonal regeneration from neural progenitor cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhengjian Yan ◽  
Lei Chu ◽  
Xiaojiong Jia ◽  
Lu Lin ◽  
Si Cheng
Keyword(s):  
Myelin Basic Protein ◽  
Neurite Outgrowth ◽  
Progenitor Cells ◽  
Axonal Regeneration ◽  
Neural Progenitor Cells ◽  
Basic Protein ◽  
Neural Progenitor ◽  
Dependent Manner ◽  
Cord Injury

Abstract Introduction Stem cell therapy using neural progenitor cells (NPCs) shows promise in mitigating the debilitating effects of spinal cord injury (SCI). Notably, myelin stimulates axonal regeneration from mammalian NPCs. This led us to hypothesize that myelin-associated proteins may contribute to axonal regeneration from NPCs. Methods We conducted an R-based bioinformatics analysis to identify key gene(s) that may participate in myelin-associated axonal regeneration from murine NPCs, which identified the serine protease myelin basic protein (Mbp). We employed E12 murine NPCs, E14 rat NPCs, and human iPSC-derived Day 1 NPCs (D1 hNPCs) with or without CRISPR/Cas9-mediated Mbp knockout in combination with rescue L1-70 overexpression, constitutively-active VP16-PPARγ2, or the PPARγ agonist ciglitazone. A murine dorsal column crush model of SCI utilizing porous collagen-based scaffolding (PCS)-seeded murine NPCs with or without stable Mbp overexpression was used to assess locomotive recovery and axonal regeneration in vivo. Results Myelin promotes axonal outgrowth from NPCs in an Mbp-dependent manner and that Mbp’s stimulatory effects on NPC neurite outgrowth are mediated by Mbp’s production of L1-70. Furthermore, we determined that Mbp/L1-70’s stimulatory effects on NPC neurite outgrowth are mediated by PPARγ-based repression of neuron differentiation-associated gene expression and PPARγ-based Erk1/2 activation. In vivo, PCS-seeded murine NPCs stably overexpressing Mbp significantly enhanced locomotive recovery and axonal regeneration in post-SCI mice. Conclusions We discovered that Mbp supports axonal regeneration from mammalian NPCs through the novel Mbp/L1cam/Pparγ signaling pathway. This study suggests that bioengineered, NPC-based interventions can promote axonal regeneration and functional recovery post-SCI.

scholarly journals DIP-2 suppresses ectopic neurite sprouting and axonal regeneration in mature neurons

2018 ◽  
Vol 218 (1) ◽  
pp. 125-133 ◽  
Author(s):  
Nathaniel Noblett ◽  
Zilu Wu ◽  
Zhao Hua Ding ◽  
Seungmee Park ◽  
Tony Roenspies ◽  
...  
Keyword(s):  
Axonal Regeneration ◽  
Neuronal Development ◽  
Adult Life ◽  
Progressive Increase ◽  
Binding Domain ◽  
Neuronal Morphology ◽  
Loss Of Function ◽  
Neuron Morphology ◽  
Interacting Protein ◽  
Mature Neurons

Neuronal morphology and circuitry established during early development must often be maintained over the entirety of animal lifespans. Compared with neuronal development, the mechanisms that maintain mature neuronal structures and architecture are little understood. The conserved disco-interacting protein 2 (DIP2) consists of a DMAP1-binding domain and two adenylate-forming domains (AFDs). We show that the Caenorhabditis elegans DIP-2 maintains morphology of mature neurons. dip-2 loss-of-function mutants display a progressive increase in ectopic neurite sprouting and branching during late larval and adult life. In adults, dip-2 also inhibits initial stages of axon regeneration cell autonomously and acts in parallel to DLK-1 MAP kinase and EFA-6 pathways. The function of DIP-2 in maintenance of neuron morphology and in axon regrowth requires its AFD domains and is independent of its DMAP1-binding domain. Our findings reveal a new conserved regulator of neuronal morphology maintenance and axon regrowth after injury.

scholarly journals Role of laminin bioavailability in the astroglial permissivity for neuritic outgrowth

2002 ◽  
Vol 74 (4) ◽  
pp. 683-690 ◽  
Author(s):  
MARCIENNE TARDY
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Neurite Outgrowth ◽  
Axonal Regeneration ◽  
Glial Scar ◽  
Reactive Astrocytes ◽  
Adult Brain ◽  
Morphological Response ◽  
Phenotypic Changes ◽  
Neuritic Outgrowth

The mechanisms involved in the failure of an adult brain to regenerate post-lesion remain poorly understood. The reactive gliosis which occurs after an injury to the CNS and leads to the glial scar has been considered as one of the major impediments to neurite outgrowth and axonal regeneration. A glial scar consists mainly of reactive, hypertrophic astrocytes. These reactive cells acquire new properties, leading to A non-permissive support for neurons. Astrogial reactivity is mainly characteriized by a high overexpression of the major component of the gliofilaments, the glial fibrillary acidic protein (GFAP). This GFAP overexpression is related to the astroglial morphological response to injury. We hypothesized that modulation of GFAP synthesis, reversing the hypertrophic phenotype, might also reverse the blockage of neuritic outgrowth observed after a lesion. In this article, we review findings of our group, confirming our hypothesis in a model of lesioned neuron-astrocyte cocultures. We demonstrate that permissivity for neuritic outgrowth is related to phenotypic changes induced in reactive astrocytes transfected by antisense GFAP-mRNA. We also found that this permissivity was related to a neuron-regulated extracellular laminin bioavailability.

Changes in properties of lamprey reticulospinal neurons following spinal cord injury

2015 ◽  
Author(s):  
◽  
Timothee Pale
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Electrical Properties ◽  
Neurite Outgrowth ◽  
Axonal Transport ◽  
Axonal Regeneration ◽  
Retrograde Axonal Transport ◽  
Slight Reduction ◽  
Synaptic Inputs ◽  
Cord Injury

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] The lamprey is one of the most ancient vertebrates, sharing many of basic characteristics of the brain and spinal cord with higher, more evolved vertebrates such as mammals. However, unlike humans and other higher vertebrates, lampreys display robust axonal regeneration in the central nervous system following spinal cord injury (SCI). For instance, axons of reticulospinal (RS) neurons in the brain can regenerate and reconnect with spinal targets leading to recovery of locomotor behavior within a few weeks following SCI. During axonal regeneration, at [about]2-3 weeks following SCI, injured RS neurons display dramatic changes in their electrical properties (i.e. "injury phenotype", absence of 2/3 afterpotentials) compared to uninjured neurons. These changes may be due to axonal injury itself, interruption of retrograde axonal transport, and/or changes in synaptic inputs. The present work will focus on several aspects of lamprey RS neurons following SCI. (1) Can activation of second messenger signaling pathways stimulate neurite outgrowth of lamprey RS neurons without altering their electrical properties? (2) Does axotomy affect Ca2+ and SK channels and their underlying conductances? (3) Are the changes in biophysical properties of RS neurons following SCI due, in part, to disruption of retrograde axonal transport? (4) Does SCI lead to changes in morphology and synaptic inputs of injured lamprey RS neurons? For lamprey RS neurons in culture, activation of cAMP pathways stimulated neurite outgrowth. In brainspinal cord preparations, forskolin resulted in action potential broadening, at least for uninjured RS neurons, which would very likely increase calcium influx. In contrast, for lamprey RS neurons, dbcAMP stimulated neurite outgrowth without altering their electrical properties. These results suggest that activation of cAMP signaling may be an effective approach for stimulating axonal regeneration of RS neurons following spinal cord injury. Our results suggest that there may be little differences in Ca2+ currents and SK currents between injured and uninjured large RS neurons. Perhaps the slight reduction in the total Ca2+ influx combined with a slight reduction of SK current (fewer activated by Ca2+) is responsible for the abolishment of the sAHP in lamprey RS neurons [about]2-3 weeks following injury. In uninjured large RS neurons that were not physically damaged by the application of the microtubuledisrupting agent vinblastine, blocking retrograde axonal transport caused some neurons to fire erratically and display the "injury phenotype", which is typical for axotomized neurons following SCI. These results suggest that retrograde axonal transport may play an important role in the maintenance of normal electrical properties in uninjured lamprey large RS neurons. Additionally, these results suggest that following SCI, interruption of retrograde axonal transport perhaps contributes to the changes in electrical properties (i.e "injury phenotype") in injured lamprey RS neurons. Injured large RS neurons did not display significant differences in the amplitudes of their synaptic responses from stimulation of the oral hood compared to uninjured neurons whether they were stimulated contralaterally or ipsilaterally, and synaptic responses of injured and uninjured RS neurons from stimulations on either the right or the left side of the oral hood were not significantly different. Taken together, these results suggest that injury does not substantially alter the synaptic inputs of injured large RS neurons. Following rostral SCI in lampreys, large injured RS neurons did not display significant changes in their basic morphology of lamprey large RS neurons. For example, the major and minor diameters of injured large RS neurons were not significantly different than those of uninjured neurons. In addition, compared to uninjured neurons, injured neurons did not have different number of primary and secondary dendrites. These results suggest that SCI does not substantially alter the basic morphology of large lamprey RS neurons. The present work provided a better understanding of the mechanisms underlying the biophysical changes of injured lamprey RS neurons during axonal regeneration. These findings could help in the development of novel therapeutic strategies to enhance axonal regeneration, following spinal cord injury in higher vertebrates, including perhaps humans.

scholarly journals Aucubin Promotes Neurite Outgrowth in Neural Stem Cells and Axonal Regeneration in Sciatic Nerves

2014 ◽  
Vol 23 (3) ◽  
pp. 238-245 ◽  
Author(s):  
Yong Min Kim ◽  
U-Cheol Sim ◽  
Yongsung Shin ◽  
Yunhee Kim Kwon
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neurite Outgrowth ◽  
Axonal Regeneration ◽  
Sciatic Nerves

Regenerating axons from adult chick retinal ganglion cells recognize topographic cues from embryonic central targets

1991 ◽  
Vol 6 (6) ◽  
pp. 569-576 ◽  
Author(s):  
Jens Vanselow ◽  
Bernhard Müller ◽  
Solon Thanos
Keyword(s):  
Retinal Ganglion Cells ◽  
Axonal Regeneration ◽  
Ganglion Cells ◽  
Target Recognition ◽  
Growth Cones ◽  
Retinal Ganglion ◽  
Embryonic Growth ◽  
Retinal Axons ◽  
Order Of Magnitude ◽  
Mature Neurons

AbstractWe investigated whether regenerating mature axons recapitulate embryonic features essential to successful reconnectivity within the injured nervous system. Strips from embryonic and adult chick retinae were cultured, and outgrowing axons were examined morphometrically and immunohistochemically. In addition, the target-recognition properties of adult neurites were analyzed. Regenerating adult axons elongate on a poly-L-lysine/laminin substratum with a speed about one order of magnitude slower than that of embryonic axons. Morphologically, adult axonal tips differ dramatically from embryonic growth cones in that they possess only filopodial extensions whereas embryonic growth cones possess both lamellipodial and filopodial processes. Both embryonic and adult neurites express the growth-associated protein GAP-43. When cultured on alternating stripes of anterior and posterior embryonic tectal membranes, both adult and embryonic retinal axons distinguish between the two membrane preparations. Our results demonstrate that during axonal regeneration the mature neurons express embryonic properties that are involved in the recognition of tectal positional cues.

Spinal Cord Injury: Lessons from Locomotor Recovery and Axonal Regeneration in Lower Vertebrates

1998 ◽  
Vol 4 (4) ◽  
pp. 250-263 ◽  
Author(s):  
Andrew D. McClellan
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neural Development ◽  
Axonal Regeneration ◽  
Spinal Cord Injuries ◽  
Axonal Guidance ◽  
Behavioral Recovery ◽  
Locomotor Function ◽  
Cord Injury ◽  
Lower Vertebrates

After severe spinal cord injury in adult higher vertebrates (birds and mammals), there normally is little or no axonal regeneration and virtually no recovery of voluntary locomotor function below the lesion. In contrast, certain lower vertebrates, including lamprey, fish, and some amphibians, exhibit robust axonal regeneration and substantial recovery of locomotor function after spinal cord injury. The remarkable behavioral recovery of lower vertebrates with spinal cord injuries is due to at least three factors: 1) minimal hemorrhagic necrosis at the injury site and the lack of a neurite growth–inhibiting astrocytic scar, 2) an environment in the spinal cord that is permissive for axonal regeneration, and 3) mechanisms for directed axonal elongation and selection of appropriate postsynaptic targets. The latter two features probably represent developmental mechanisms for axonal guidance and synaptogenesis that persist in the nervous systems of these animals well beyond the main phase of neural development. In the injured spinal cords of higher vertebrates, the full complement of manipulations necessary to promote functional regeneration and behavioral recovery is unknown. An understanding of the mechanisms that result in repair of spinal cord injuries in lower vertebrates may provide guidelines for identifying the requirements for functional spinal cord regeneration in higher vertebrates, including humans.

scholarly journals Treatment of Stroke with a Synthetic Liver X Receptor Agonist, TO901317, Promotes Synaptic Plasticity and Axonal Regeneration in Mice

2009 ◽  
Vol 30 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Jieli Chen ◽  
Alex Zacharek ◽  
Xu Cui ◽  
Amjad Shehadah ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Neurite Outgrowth ◽  
Axonal Regeneration ◽  
Artery Occlusion ◽  
Phosphatidylinositol 3 Kinase ◽  
Ischemic Brain ◽  
Pi3k Activity ◽  
Synapse Plasticity ◽  
Cerebral Artery Occlusion ◽  
Liver X Receptor Agonist

In this study, we tested the hypothesis that TO901317 promotes synapse plasticity and axonal regeneration after stroke. Adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and treated with or without TO901317 starting 24 h after MCAo daily for 14 days. Axonal damage and regeneration were evaluated by immunostaining. TO901317 significantly increased synaptophysin expression and axonal regeneration, as well as decreased the expressions of amyloid betaA4 precursor protein and Nogo receptor (NgR) in the ischemic brain. To test whether TO901317 regulates the phosphorylation of phosphatidylinositol 3-kinase (p-PI3K) and Akt (p-Akt) activity in the ischemic brain, MCAo mice were treated with or without TO901317 starting 24 h after MCAo daily for 4 days and were then killed at 5 days after MCAo. TO901317 treatment significantly increased p-PI3K and p-Akt activity, but did not increase total PI3K expression in the ischemic brain. Using primary cortical neuron (PCN) culture, TO901317 significantly increased synaptophysin expression, p-PI3K activity, and decreased NgR expression compared with nontreated controls. TO901317 also significantly increased neurite outgrowth, and inhibition of the PI3K/Akt pathway by LY294002 decreased neurite outgrowth in both controls and TO901317-treated groups in cultured hypoxic PCN. These data indicate that TO901317 promotes synaptic plasticity and axonal regeneration, and that PI3K/Akt signaling activity contributes to neurite outgrowth.

scholarly journals SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway

2012 ◽  
Vol 23 (23) ◽  
pp. 4506-4514 ◽  
Author(s):  
Yonghua Liu ◽  
Ying Chen ◽  
Xiang Lu ◽  
Youhua Wang ◽  
Yinong Duan ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Cortical Neurons ◽  
Axonal Regeneration ◽  
P53 Protein ◽  
Transcriptional Activator ◽  
Small Interfering Rnas ◽  
P53 Pathway ◽  
Neuronal Morphogenesis

SCY1-like 1–binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing a protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is required for neurite outgrowth and regeneration. Here we present evidence that SCYL1BP1 inhibits nerve growth factor–mediated neurite outgrowth in PC12 cells and affects morphogenesis of primary cortical neurons by strongly decreasing the p53 protein level in vitro, all of which depends on SCYL1BP1's transcriptional activator domain. Exogenous p53 rescues neurite outgrowth and neuronal morphogenesis defects caused by SCYL1BP1. Furthermore, SCYL1BP1 can directly induce Mdm2 transcription, whereas inhibiting the function of Mdm2 by specific small interfering RNAs results in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by SCYL1BP1. In vivo experiments show that SCYL1BP1 can also depress axonal regeneration, whereas inhibiting the function of SCYL1BP1 by specific short hairpin RNA enhances it. Taken together, these data strongly suggested that SCYL1BP1 is a novel transcriptional activator in neurite outgrowth by directly modulating the Mdm2/p53-dependent pathway, which might play an important role in CNS development and axonal regeneration after injury.

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