The Conditioning Lesion Response in Dorsal Root Ganglion Neurons Is Inhibited in Oncomodulin Knock-Out Mice

Niemi, Jon P.; DeFrancesco-Oranburg, Talia; Cox, Andrew M.; Lindborg, Jane A.; Echevarria, Franklin D.; McCluskey, Jemima; Simmons, Dwayne D.; Zigmond, Richard E.

doi:10.1523/eneuro.0477-21.2022

Cited by 9 publications

(10 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the IL-6 knockout study directly indicates the key role of IL-6 in enhancing the regeneration of dorsal column axons in conditioning lesions. cAMP upregulation after injury directly mediates the release of IL-6 and induces activation of downstream pathways for STAT3 and, ultimately Gap-43 [ 26 , 27 , 28 ].…”

Section: Molecular Pathways and Therapeutic Targetsmentioning

confidence: 99%

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

et al. 2022

View full text Add to dashboard Cite

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.

show abstract

Section: Molecular Pathways and Therapeutic Targetsmentioning

confidence: 99%

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The innate immune system is important for peripheral nerve regeneration (6)(7)(8) and, in the CNS, enables retinal ganglion cells (RGCs) to extend axons through the injured optic nerve (9,10) and DRG neurons to regenerate central axons in the injured spinal cord after a conditioning peripheral nerve lesion (3,4,11). The 12-kDa protein oncomodulin (Ocm) plays a central role in these phenomena (4,(12)(13)(14)(15). Upon secretion from myeloid cells, Ocm exhibits adenosine 3 0 ,5 0 -monophosphate (cAMP)-dependent, high-affinity binding to an unidentified receptor on RGCs (12) and, when combined with a cAMP analog and stromal cell-derived factor 1 (SDF1), fully mimics inflammation-induced optic nerve regeneration (16).…”

Section: Introductionmentioning

confidence: 99%

The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC–derived sensory neurons

Xie,

Yin,

Jayakar

et al. 2023

Sci. Transl. Med.

View full text Add to dashboard Cite

Oncomodulin (Ocm) is a myeloid cell–derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell–derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.

show abstract

“…Unlike RGCs, sensory neurons of the dorsal root ganglia (DRG) can regenerate their peripheral axon branches after sciatic nerve injury, and a conditioning peripheral nerve injury potentiates the ability of sensory neurons both to regenerate their peripheral axon branches after a second injury and to regenerate their central axon branches after spinal cord injury (17,18). This phenomenon is partly driven by infiltrative immune cells (19)(20)(21)(22) and represents one of the strongest paradigms for spinal cord regeneration (23). Here, we investigated whether inflammatory preconditioning by zymosan or lens injury would enable axon regeneration in the mouse ONC model and examined whether perturbation of major immune cell types and known immune cell-derived growth factors affect regeneration using pharmacological or genetic manipulations.…”

Section: Introductionmentioning

confidence: 99%

Full-length optic nerve regeneration in the absence of genetic manipulations

Feng¹,

Wong²,

Benowitz³

2023

JCI Insight

View full text Add to dashboard Cite

The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -non-autonomous factors. Although manipulations of cell-non-autonomous factors could have higher translational potential than genetic manipulations of RGCs, they have generally produced lower levels of optic nerve regeneration. Here we report that preconditioning resulting from mild lens injury (conditioning LI, cLI) prior to optic nerve damage induces far greater regeneration than LI after nerve injury or the pro-inflammatory agent zymosan given either before or after nerve damage. Unlike zymosan-induced regeneration, cLI is unaltered by depleting mature neutrophils or T cells or blocking receptors for known inflammation-derived growth factors (Oncomodulin, SDF1, CCL5), and is only partly diminished by suppressing CCR2+ monocyte recruitment. Repeated episodes of LI lead to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 enables some axons to re-innervate the brain in just 6 weeks, comparable to the results obtained with the most effective genetic manipulations of RGCs. Thus, cell-non-autonomous interventions can induce high levels of optic nerve regeneration, paving the way to uncover potent, translatable therapeutic targets for CNS repair.

show abstract

The Conditioning Lesion Response in Dorsal Root Ganglion Neurons Is Inhibited in Oncomodulin Knock-Out Mice

Cited by 9 publications

References 53 publications

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC–derived sensory neurons

Full-length optic nerve regeneration in the absence of genetic manipulations

Contact Info

Product

Resources

About