Retinoic acid signaling in axonal regeneration

Radhika Puttagunta,Simone Di Giovanni

doi:10.3389/fnmol.2011.00059

Radhika Puttagunta, Simone Di Giovanni

Open Access

https://doi.org/10.3389/fnmol.2011.00059

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Abstract

Following an acute central nervous system (CNS) injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. Retinoic acid (RA) signaling, essential in developmental dorsoventral patterning and specification of spinal motor neurons, has been shown through its receptor, the transcription factor RA receptor β2 (RARβ2), to induce axonal regeneration following spinal cord injury (SCI). Recently, it has been shown that in dorsal root ganglion neurons (DRGs), cAMP levels were greatly increased by lentiviral RARβ2 expression and contributed to neurite outgrowth. Moreover, RARβagonists, in cerebellar granule neurons (CGN) and in the brain in vivo, induced phosphoinositide 3-kinase dependent phosphorylation of AKT that was involved in RARβ-dependent neurite outgrowth. More recently, RA-RARβpathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor (NgR) complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field.

Highlights

The limited regenerative capacity observed following an acute central nervous system (CNS) lesion, such as stroke or brain/spinal cord traumatic injuries, is due to both the presence of an extrinsic inhibitory growth environment and the lack of intrinsic growth factors
The neuronal insulating layer, myelin, is fragmented following a CNS lesion, releasing the extrinsic inhibitory molecules, myelin associated glycoprotein (MAG), Nogo, and Oligodendrocyte myelin glycoprotein (OMgp) (DeBellard et al, 1996; Huber and Schwab, 2000; Wang et al, 2002; He et al, 2003) that inhibit axonal outgrowth and functional recovery following injury. These myelin proteins signal through the neuronal membrane bound Nogo Receptor (NgR) complex, which includes NgR1 (Chen et al, 2000; GrandPre et al, 2000), Lingo-1 (Mi et al, 2004), and p75NTR (Domeniconi et al, 2002; Wong et al, 2002) or TROY (Park et al, 2005)
While it is known that Retinoic acid (RA) signaling does induce neurite outgrowth and axonal regeneration only limited research has been done on the precise molecular mechanisms involved

Summary

Retinoic acid signaling in axonal regeneration

Following an acute central nervous system (CNS) injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. RA-RARβ pathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor (NgR) complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field

INTRODUCTION

RA signaling in axonal regeneration

THE MOLECULAR MECHANISMS OF RA SIGNALING IN AXONAL REGENERATION

RA AND EPIGENETICS

RA Conditioning lesion

Protein synthesis Cell growth