The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Fawcett, James W.

doi:10.1007/s11064-019-02844-y

Cited by 99 publications

(72 citation statements)

References 146 publications

(129 reference statements)

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“…Previous results showed that Nystatin increases axon regeneration post-axotomy in primary cell cultures of hippocampal neurons (Roselló-Busquets et al, 2019). The ability of axons to regenerate is lost in adult CNS neurons (He and Jin, 2016;Curcio and Bradke, 2018;Fawcett, 2019). Primary CNS neuronal cultures lose their regenerative capacities during their in vitro differentiation (del Rio and Soriano, 2010).…”

Section: Nystatin Increases Axon Regeneration In Immature and Differementioning

confidence: 99%

Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide

Roselló-Busquets

Hernaiz-Llorens

Soriano

et al. 2020

Front. Mol. Neurosci.

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Nystatin is a pharmacological agent commonly used for the treatment of oral, mucosal and cutaneous fungal infections. Nystatin has also been extensively applied to study the cellular function of cholesterol-enriched structures because of its ability to bind and extract cholesterol from mammalian membranes. In neurons, cholesterol level is tightly regulated, being essential for synapse and dendrite formation, and axonal guidance. However, the action of Nystatin on axon regeneration has been poorly evaluated. Here, we examine the effect of Nystatin on primary cultures of hippocampal neurons, showing how acute dose (minutes) of Nystatin increases the area of growth cones, and chronic treatment (days) enhances axon length, axon branching, and axon regeneration postaxotomy. We describe two alternative signaling pathways responsible for the observed effects and activated at different concentrations of Nystatin. At elevated concentrations, Nystatin promotes growth cone expansion through phosphorylation of Akt; whereas, at low concentrations, Nystatin enhances axon length and regrowth by increasing nitric oxide levels. Together, our findings indicate new signaling pathways of Nystatin and propose this compound as a novel regulator of axon regeneration.

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Section: Nystatin Increases Axon Regeneration In Immature and Differementioning

confidence: 99%

Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide

Roselló-Busquets

Hernaiz-Llorens

Soriano

et al. 2020

Front. Mol. Neurosci.

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“…Axonal regeneration in the CNS is inhibited by several inhibitory molecules released in the CNS microenvironment after injury. Among these, chondroitin sulphate proteoglycans (CSPGs) are released by glia cells, myelin associated glycoprotein (MAG) by myelinating glia and oligodendrocyte myelin glycoprotein (OMgp) by oligodendrocytes [136]. Furthermore, astrocytes become reactive producing a glial scar following neuronal cell death induced by injury [137].…”

Section: Egfr Functions After Injury and Its Role In Regenerationmentioning

confidence: 99%

Role of EGFR in the Nervous System

Romanò

Bucci

2020

Cells

117

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Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of EGFR in the regulation of tissue development and homeostasis has been thoroughly investigated and it has also been demonstrated that EGFR is a driver of tumorigenesis. In the nervous system, other growth factors, and thus other receptors, are important for growth, differentiation and repair of the tissue, namely neurotrophins and neurotrophins receptors. For this reason, for a long time, the role of EGFR in the nervous system has been underestimated and poorly investigated. However, EGFR is expressed both in the central and peripheral nervous systems and it has been demonstrated to have specific important neurotrophic functions, in particular in the central nervous system. This review discusses the role of EGFR in regulating differentiation and functions of neurons and neuroglia. Furthermore, its involvement in regeneration after injury and in the onset of neurodegenerative diseases is examined.

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“…Studies aimed at enhancing CNS regeneration have identified transcriptional and epigenetic programs 6,7 , signalling pathways [8][9][10] , the cytoskeleton [11][12][13][14] and axon transport [15][16][17][18][19] as important factors governing regenerative ability. However, the precise machinery required to reconstitute and extend an injured axon is not completely understood, and repairing the injured CNS remains a challenging objective 20 .…”

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confidence: 99%

Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

et al. 2020

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Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.

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The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Cited by 99 publications

References 146 publications

Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide

Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide

Role of EGFR in the Nervous System

Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

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