Retinoic acid signaling in axonal regeneration

Frontiers in Molecular Neuroscience, 2012 · DOI: 10.3389/fnmol.2011.00059 · Published: January 3, 2012

Regenerative Medicine Neurology Genetics

Simple Explanation

Following an acute central nervous system (CNS) injury, axonal regeneration and functional recovery are extremely limited due to an 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). 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.

Study Duration

Not specified

Participants

Adult rat DRGs, sensorimotor cortex, brain treated rats, wildtype and RARβ null mice, postnatal CGN

Evidence Level

Not specified

Key Findings

1
RARβ2 lentiviral infection of adult rat DRGs induced axonal growth and functional recovery of injured sensory neurons into the dorsal root entry zone (DREZ) following dorsal root lesion.
2
RARβ2 null mice have less axonal regeneration following a peripheral nerve crush versus wildtype mice.
3
RA signaling increases neurite outgrowth, decreases RhoA activation and inhibits Lingo-1 gene and protein expression in a myelin-inhibitory environment, speciﬁcally through RARβ.

Research Summary

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). 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.

Practical Implications

Overcoming Myelin Inhibition

RA-RARβ pathway overcomes the myelin inhibitory environment, potentially promoting axonal regeneration after SCI.

Enhancing Intrinsic Neuronal Capacity

RA-RARβ signaling may enhance the intrinsic ability of CNS neurons to regenerate by driving the expression of specific RAGs.

Reducing Inflammation

RA has anti-inflammatory benefits and may reduce glial scar formation after SCI by inhibiting the inflammatory response.

Study Limitations

1
RA-RARβ pathway seems to overcome the myelin inhibitory environment, but not necessarily proteoglycan inhibitory signaling.
2
Further investigation is needed to clarify more direct transcriptional targets of RA-RARβ signaling following SCI
3
The relative weight of paracrine or autocrine pathways in axonal regeneration warrants further investigation.

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