Regulating Axonal Responses to Injury: The Intersection between Signaling Pathways Involved in Axon Myelination and The Inhibition of Axon Regeneration

Abstract

Following spinal cord injury (SCI), a multitude of intrinsic and extrinsic factors adversely affect the gene programs that govern the expression of regeneration-associated genes (RAGs) and the production of a diversity of extracellular matrix molecules (ECM). Insufficient RAG expression in the injured neuron and the presence of inhibitory ECM at the lesion, leads to structural alterations in the axon that perturb the growth machinery, or form an extraneous barrier to axonal regeneration, respectively. Here, the role of myelin, both intact and debris, in antagonizing axon regeneration has been the focus of numerous investigations. These studies have employed antagonizing antibodies and knockout animals to examine how the growth cone of the re-growing axon responds to the presence of myelin and myelin-associated inhibitors (MAIs) within the lesion environment and caudal spinal cord. However, less attention has been placed on how the myelination of the axon after SCI, whether by endogenous glia or exogenously implanted glia, may alter axon regeneration. Here, we examine the intersection between intracellular signaling pathways in neurons and glia that are involved in axon myelination and axon growth, to provide greater insight into how interrogating this complex network of molecular interactions may lead to new therapeutics targeting SCI.

PirB inhibits axonal outgrowth via the PI3K/Akt/mTOR signaling pathway

“…Accumulating evidence suggests that the lack of regeneration capacity in the adult mammalian CNS is due to the presence of certain myelin-derived inhibitors, including the repulsive trio (Nogo-66, MAG and OMgp) (4,5). Inhibitory signaling is transduced via their receptors, NgR and PirB.…”

“…CNS axons have regeneration capacity, but fail to regenerate predominantly due to environment obstacles that inhibit axonal regeneration after injury (3). It is reported that the inhibitory activity is closely associated with CNS myelin components and other molecules at the injury site (4). The three myelin-derived inhibitors, reticulon 4 (Nogo), myelinassociated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), are potential inhibitors of axonal outgrowth in vitro; they interact with the lycosylphosphatidylinositol-anchored Nogo receptor (NgR) via their C-terminal 66-residue loops (Nogo-66) (5).…”

Wallerian demyelination: chronicle of a cellular cataclysm

“…Indeed the smallest cut may easily sever a nerve bundle in the skin leading to pain, axonal degeneration, and Schwann cells demyelination. In peripheral nerves, neuronal plasticity allows axons to grow back and the nerve bundle to regenerate [ 1 ]. However, elimination of myelin is critical as myelin proteins are known to inhibit axonal regeneration [ 1 ].…”

“…In peripheral nerves, neuronal plasticity allows axons to grow back and the nerve bundle to regenerate [ 1 ]. However, elimination of myelin is critical as myelin proteins are known to inhibit axonal regeneration [ 1 ]. Finally, demyelinated Schwann cells then remyelinate axons to restore the full nerve function.…”

Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury

“…After damage to the peripheral nervous system, Schwann cells dedifferentiate into an immature cell type, proliferate to generate a larger population, and digest axon and myelin sheath debris to clear a regenerative path for subsequent axon regrowth Mirsky, 2008, 2016;Napoli et al, 2012). Schwann cells then migrate along and wrap around the regrown axons, establish a 1:1 ratio with axons, and undergo redifferentiation and myelination (Ness et al, 2013;Rao and Pearse, 2016). The phenotypes of Schwann cells can be modulated by various cellular and molecular factors, such as the neurotrophic factors nerve growth factor (Li et al, 2015) and brain-derived neurotrophic factor (Yi et al, 2016b).…”