Retinoic acid synthesis by NG2 expressing cells promotes a permissive environment for axonal outgrowth

Neurobiology of Disease, 2018 · DOI: https://doi.org/10.1016/j.nbd.2017.12.016 · Published: March 1, 2018

Regenerative Medicine Neurology Genetics

Simple Explanation

This study identifies a novel mechanism by which neuronal RARβ activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Neuronal RARβ activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth.

Study Duration

4 weeks

Participants

Male Sprague-Dawley rats

Evidence Level

Not specified

Key Findings

1
Neuronal RARβ activation induces endogenous RA signaling in NG2+ cells and neurons at the injury site after spinal cord injury.
2
RA paracrine signaling initiated by RARβ activation has an important effect on axonal outgrowth.
3
The release of exosomes from NG2+ cells controls RA paracrine signaling.

Research Summary

This study demonstrates that one of the signaling cascades induced by RARβ activation in injured neurons is endogenous RA signaling in NG2+ cells and neurons at the injury site. The RA paracrine signaling initiated by RARβ activation has an important effect on axonal outgrowth and is controlled by the release of exosomes from NG2+ cells. The study identifies a novel mechanism of interplay between neurons and NG2+ glia whereby synthesis and transfer of RA is controlled by the activity of both cell types who in synergy promote axonal growth and guidance.

Practical Implications

Therapeutic Target Identification

RARβ and the subsequent modulation of RA synthesis at the injury site could represent important therapeutic targets for CNS regeneration.

Shortened Treatment Duration

An RARβ agonist could be administered for a much shorter period than the one required for the full regeneration of the axon, as the endogenous RA signalling would maintain the required axonal growth thereafter.

Autonomous Regeneration Mechanism

The identiﬁcation of an autonomous mechanism that perpetuates axonal regeneration is of utmost importance in translational medicine

Study Limitations

1
The overall eﬀect of NG2+ cells in axonal regeneration seems to depend largely on their phenotype which can yield dichotomic responses.
2
The challenge in human spinal cord regeneration is the long distance the axons need to grow thus requiring lengthy treatments.
3
The speciﬁc distribution of the ADH7 and Raldh2 is therefore paramount in this assembly.

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