Exogenous Modulation of Retinoic Acid Signaling Affects Adult RGC Survival in the Frog Visual System after Optic Nerve Injury.

Mildred V Duprey-Díaz,Jonathan M Blagburn,Rosa E Blanco,Filippo Del Bene

doi:10.1371/journal.pone.0162626

Mildred V Duprey-Díaz, Jonathan M Blagburn + Show 2 more

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https://doi.org/10.1371/journal.pone.0162626

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Abstract

After lesions to the mammalian optic nerve, the great majority of retinal ganglion cells (RGCs) die before their axons have even had a chance to regenerate. Frog RGCs, on the other hand, suffer only an approximately 50% cell loss, and we have previously investigated the mechanisms by which the application of growth factors can increase their survival rate. Retinoic acid (RA) is a vitamin A-derived lipophilic molecule that plays major roles during development of the nervous system. The RA signaling pathway is also present in parts of the adult nervous system, and components of it are upregulated after injury in peripheral nerves but not in the CNS. Here we investigate whether RA signaling affects long-term RGC survival at 6 weeks after axotomy. Intraocular injection of all-trans retinoic acid (ATRA), the retinoic acid receptor (RAR) type-α agonist AM80, the RARβ agonist CD2314, or the RARγ agonist CD1530, returned axotomized RGC numbers to almost normal levels. On the other hand, inhibition of RA synthesis with disulfiram, or of RAR receptors with the pan-RAR antagonist Ro-41-5253, or the RARβ antagonist LE135E, greatly reduced the survival of the axotomized neurons. Axotomy elicited a strong activation of the MAPK, STAT3 and AKT pathways; this activation was prevented by disulfiram or by RAR antagonists. Finally, addition of exogenous ATRA stimulated the activation of the first two of these pathways. Future experiments will investigate whether these strong survival-promoting effects of RA are mediated via the upregulation of neurotrophins.

Highlights

Retinoic acid (RA) is a vitamin A-derived lipophilic molecule that plays a major role during early development of the nervous system, setting up dorsoventral and anteroposterior patterning of the neural plate and tube [1]
The RARβ antagonist did not significantly reduce survival more than did retinaldehyde dehydrogenase (RALDH) inhibition (p = 0.708). These results suggest that the subpopulation of retinal ganglion cells (RGCs) that depend on endogenous RA for survival do require retinoic acid receptor (RAR), some which are of the β subtype
We have shown here that long-term survival of axotomized RGCs is returned to almost normal levels by treatment with RA, or with agonists for its receptors

Summary

Introduction

Retinoic acid (RA) is a vitamin A-derived lipophilic molecule that plays a major role during early development of the nervous system, setting up dorsoventral and anteroposterior patterning of the neural plate and tube [1]. Its later function is to direct the differentiation of various types of neurons and glia by activating the transcription of many genes, including those that encode transcription factors, cell signaling molecules, enzymes and cell surface receptors [1,2,3,4,5]. Retinoic Acid Signaling Increases Adult RGC Survival after Axotomy

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