The Nogo Receptor Pathway in Central Nervous System Axon Regeneration and Therapeutic Opportunities

Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.

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Tracing Central Nervous System Axon Regeneration in Xenopus

Cold Spring Harbor Protocols ◽

10.1101/pdb.prot101030 ◽

2018 ◽

Vol 2018 (12) ◽

pp. pdb.prot101030 ◽

Cited By ~ 1

Author(s):

Kurt M. Gibbs ◽

Ben G. Szaro

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axon Regeneration

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Source of Early Regenerating Axons in Lamprey Spinal Cord Revealed by Wholemount Optical Clearing with BABB

Cells ◽

10.3390/cells9112427 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2427 ◽

Cited By ~ 1

Author(s):

Guixin Zhang ◽

William Rodemer ◽

Isabelle Sinitsa ◽

Jianli Hu ◽

Michael E. Selzer

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Confocal Microscopy ◽

Axon Regeneration ◽

Benzyl Benzoate ◽

Optical Clearing ◽

Propriospinal Neurons ◽

Early Regeneration ◽

Anterograde Labeling

Many studies of axon regeneration in the lamprey focus on 18 pairs of large identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Their axons retract during the first 2 weeks after transection (TX), and many grow back to the site of injury by 4 weeks. However, locomotor movements begin before 4 weeks and the lesion is invaded by axons as early as 2 weeks post-TX. The origins of these early regenerating axons are unknown. Their identification could be facilitated by studies in central nervous system (CNS) wholemounts, particularly if spatial resolution and examination by confocal microscopy were not limited by light scattering. We have used benzyl alcohol/benzyl benzoate (BABB) clearing to enhance the resolution of neuronal perikarya and regenerated axons by confocal microscopy in lamprey CNS wholemounts, and to assess axon regeneration by retrograde and anterograde labeling with fluorescent dye applied to a second TX caudal or rostral to the original lesion, respectively. We found that over 50% of the early regenerating axons belonged to small neurons in the brainstem. Some propriospinal neurons located close to the TX also contributed to early regeneration. The number of early regenerating propriospinal neurons decreased with distance from the original lesion. Descending axons from the brainstem were labeled anterogradely by application of tracer to a second TX close to the spinal–medullary junction. This limited contamination of the data by regenerating spinal axons whose cell bodies are located rostral or caudal to the TX and confirmed the regeneration of many small RS axons as early as 2 weeks post-TX. Compared with the behavior of axotomized giant axons, the early regenerating axons were of small caliber and showed little retraction, probably because they resealed rapidly after injury.

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Peripheral nerve grafts to the frog optic tectum: A morphological study of foreign axon regeneration in the central nervous system

The Journal of Comparative Neurology ◽

10.1002/cne.902350310 ◽

1985 ◽

Vol 235 (3) ◽

pp. 395-415 ◽

Cited By ~ 4

Author(s):

Elliot I. Kaplan ◽

Carmine D. Clemente

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Peripheral Nerve ◽

Optic Tectum ◽

Morphological Study ◽

Axon Regeneration ◽

Nerve Grafts ◽

Peripheral Nerve Grafts ◽

The Central Nervous System

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Adult Mouse Retina Explants: From ex vivo to in vivo Model of Central Nervous System Injuries

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.599948 ◽

2020 ◽

Vol 13 ◽

Author(s):

Julia Schaeffer ◽

Céline Delpech ◽

Floriane Albert ◽

Stephane Belin ◽

Homaira Nawabi

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Molecular Mechanisms ◽

Axon Regeneration ◽

Ex Vivo ◽

Mouse Retina ◽

In Vivo Model ◽

Cns Regeneration ◽

Single Axon

In mammals, adult neurons fail to regenerate following any insult to adult central nervous system (CNS), which leads to a permanent and irreversible loss of motor and cognitive functions. For a long time, much effort has been deployed to uncover mechanisms of axon regeneration in the CNS. Even if some cases of functional recovery have been reported, there is still a discrepancy regarding the functionality of a neuronal circuit upon lesion. Today, there is a need not only to identify new molecules implicated in adult CNS axon regeneration, but also to decipher the fine molecular mechanisms associated with regeneration failure. Here, we propose to use cultures of adult retina explants to study all molecular and cellular mechanisms that occur during CNS regeneration. We show that adult retinal explant cultures have the advantages to (i) recapitulate all the features observed in vivo, including axon regeneration induced by intrinsic factors, and (ii) be an ex vivo set-up with high accessibility and many downstream applications. Thanks to several examples, we demonstrate that adult explants can be used to address many questions, such as axon guidance, growth cone formation and cytoskeleton dynamics. Using laser guided ablation of a single axon, axonal injury can be performed at a single axon level, which allows to record early and late molecular events that occur after the lesion. Our model is the ideal tool to study all molecular and cellular events that occur during CNS regeneration at a single-axon level, which is currently not doable in vivo. It is extremely valuable to address unanswered questions of neuroprotection and neuroregeneration in the context of CNS lesion and neurodegenerative diseases.

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