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.
Highlights
The current review examines the distinct signaling pathways implicated in axonglia communication during myelination, and discusses how these same pathways play a role in altering axonal growth responses after injury
Axon-glial communications during the myelination process affect two critical decisions in axonal growth. The first of these are the signals for ensheathment and myelination of the axon that originate in axons themselves, while the second are signals that inhibit longitudinal growth to promote radial growth of the axon that originate from glia
Studies have highlighted the importance of PI3K/Akt in the myelination program and ERK/p38MAPK in axonal growth
Summary
Neuron-glia interactions have been fundamental to the structure and function of the brain throughout evolution (Herculano-Houzel, 2014). Myelination is a multistage process with considerable overlap among its different phases These phases involve: (1) the migration and ensuing differentiation of glial precursors into mature myelinating glia; (2) the initial recognition of the axon, axon-glia contact, axonal segment selection and subsequent ensheathment of the target axonal segments by the myelinating glia; (3) the initiation of myelinassociated protein expression in the myelinating glia and ; (4) the compaction and maturation of the myelin sheath (Szuchet et al, 2015). Myelin protein zero (P0/MPZ) and peripheral myelin protein (PMP22) constitute characteristic structural proteins of peripheral myelin (Patzig et al, 2011) Despite these structural and composition differences, axonal signaling plays an important role in the regulation of both OL and SC development, myelin biogenesis and their ability to myelinate CNS and the PNS axons, respectively (Barres and Raff, 1999; Nave and Trapp, 2008; Taveggia et al, 2010). The current review examines the distinct signaling pathways implicated in axonglia communication during myelination, and discusses how these same pathways play a role in altering axonal growth responses after injury
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