Activation from its functioning myelination form, to a Schwann

 Activation of the c-Jun gene in Schwann cells is essential to the regeneration process (Arthur-Farraj et al, 2012). C-Jun signals the Schwann cell to reprogram from its functioning myelination form, to a Schwann cell which functions specifically to induce regeneration  These specialized Schwann cells breakdown the myelin surrounding the injury and instruct macrophages to clear the debris and inhibitory growth factors  In addition to clearing the damaged area, the reprogrammed Schwann cells, and recruited macrophages, promote proliferation by producing neurotrophic growth factors (Benga et al, 2017).  In the central nervous system, nerves are myelinated with oligodendrocytes as opposed to Schwann cells (Bradl & Lassmann). Unlike Schwann cells, oligodendrocytes are not reprogrammed to promote regeneration or clean the damaged area of debris following axotomy (Silver, Schwab, & Popvich, 2015), the severing of an axon that occurs in Wallerian degeneration (Anon, 2013). Additionally reducing the likelihood of regeneration are the oligodendrocytes and the myelin produced in the central nervous system which contain inhibitory factors rather than growth factors. When a nerve is damaged, these inhibitory factors prevent regeneration in the affected axon (Silver, Schwab, & Popvich, 2015).  The peripheral nervous system is host to a wide variety of growth factors, many of which are produced in excess after an axonal injury (Terenghi, 1998). Neurotrophins are one family of growth factors shown to have significant impact on nerve repair in the PNS. All neurotrophins share a similar structure, including six conserved cysteine residues, and act with low affinity on p75 and high affinity on tyrosine kinase receptors (Rush, Mayo, & Zettler, 2003). Two neurotrophins, NGF and NT-3, among others, are produced by Schwann cells in surplus following a PNS nerve injury (Johnson & Tuszyski, 2008). Neurotrophic presence has been shown to impact the density and pattern of neurite outgrowth in both motor and sensory axons (Rush, Mayo, & Zettler 2013). Another fundamental growth factor is serum response factor, SRF, discovered to have multiple effects on the regeneration process. As a nuclear transcription factor, SRF activates genes required for structural changes to the cytoskeleton, a process necessary for the regain of function in the PNS (Knoll & Nordheim, 2009). The regeneration aspects of SRF require the growth factor to be translocated to the cytoplasm. Once in the cytoplasm, SRF plays a vital role in enhancing neurite outgrowth as well as the size and motility of the growth cone (Stern et al, 2013). Contrary to the peripheral nervous system, there are few growth factors to regenerate axons in the CNS. Inhibitory factors are plentiful, however, as they are not phagocytized after the injury (Tanaka, Ueno, & Yamashita, 2009.). Nogo-A, found in oligodendrocytes and CNS myelin, is known to be a potent regeneration inhibitor (Huber & Schwab, 2000). It acts on a receptor complex of p75, Troy, and Lingo on the surface of the injured axon to inhibit growth cone production and neurite outgrowth (Schwab & Strittmater, 2014). Other inhibitory factors are found within the extracellular matrix, ECM, of the central nervous system, creating an environment around the damaged axon that opposes regeneration. It is important to note that these factors are not present in the ECM of the PNS (Figure 1). The factors of the CNS ECM shown to have the most significant growth inhibitory impact are chronditin sulfate proteoglycan molecules, CSPGs. CSPGs are only found within the CNS (Neikerk et al, 2016).           The peripheral nervous system is capable of regenerating axons across both short and long distances (Bradbury, 2017). Many of these newly grown axons originate in the injured area of the nerve due to the presence of growth factors previously described (Benga et al, 2017). The first part section of the regenerated axon synthesized is the actin-rich growth cone. The growth cone originates in the end of the injured axon and has many functions (Neikerk et al, 2016). To ensure it has optimal responsiveness to the surrounding environment, the growth cone has the ability to control the expression of its growth factor receptors (Ebadi et al, 1997). Once the axon begins to extend from the proximal section towards the distal stump, ephrins, semaphorins, slits, and netrins provide attractive and repulsive signals (Kaselis & Satkauskas, 2013). The growing axon responds accordingly to the growth factors and guidance molecules as it travels from along the endoneurial tube, a connective tissue layer around the myelin sheath of the axon. It is important to note that the endoneurium is the only part of the distal axon not degenerated after the injury (Fisher, Mikos, & Bronzino, 2007). In the central nervous system, the limited axon regeneration that does occur is in the form of short “sprouts” of axons across very short distances (Fitch & Silver, 2008). The majority of these axons originate in healthy nerves nearby in an attempt to compensate for the damaged nerve (Jain, 2000). No long-distance axon regeneration is observed due to the inability of injured CNS nerves to initiate growth cones (Neikerk et al, 2016).  A critical chemical and physical barrier to axon regeneration in the central nervous system is the formation of a glial scar (Fitch & Silver, 2008). The glial scar is formed following Wallerian degeneration in the CNS. It is composed of astrocytes, oligodendrocytes, oligodendrocyte precursor cells, microglia, and meningeal cells, all of which have growth inhibitory properties. The cells creating the majority of the glial scar, however, are astrocytes connected by gap junctions and tight junctions (Fawcett & Asher, 1999). When a lesion develops in the CNS, the blood brain barrier is damaged, releasing blood and serum elements into the injured area (Cregg et al, 2014). It is hypothesized that these elements induce the formation of the glial scar, especially fibrinogen-TGF? complex which is directly connected to astrogliosis (Schachtrup et al, 2010), an increase in astrocyte proliferation (Anon, 2012). As the astrocytes divide, grow, and extend their processes, a network is created. This network encompasses the other molecules in the area, including the myelin debris and the inhibitory cells mentioned, and forms the glial scar (Fawcett & Asher, 1999).