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neurotrophic factor, leukemia inhibitory factor, and interleukin-6 at the
injury sites; elevation of intracellular second messengers such as cyclic
adenosine monophosphate (cAMP); and activation of axonal and nuclear
transport proteins including vimentin, importins, and RanGTPase, play
critical roles in promoting regenerative responses (
Sun &He, 2010
). Recent
studies also demonstrated the stimulation of axon repair and growth by
inflammatory response (
Yin et al., 2006
).
1.3. Extrinsic and intrinsic determinants of axon regeneration
Although axotomy-induced expression of cytokines is necessary for activat-
ing axon regeneration, exogenous delivery of cytokines is not sufficient to
enhance regenerative capacity of damaged central nervous system (CNS)
neurons following either optic nerve injury or spinal cord injury, which
are the two major
in vivo
animal models for axon regeneration. It appears that
damaged axons cannot regenerate in the mammalian CNS following injury,
whereas axons of the peripheral nervous system (PNS) retain the capability to
sprout and regrow toward appropriate targets. To explain such difference,
one hypothesis is that the nonpermissive nature of CNS tissue, rather than
their intrinsic inability to grow, prevents mammalian CNS neurons from re-
generation. Indeed, some CNS neurons such as retinal ganglion cells (RGCs)
exhibit different levels of regeneration after axon cut invarious culturemodels
(
Chierzi, Ratto, Verma, & Fawcett, 2005
). Therefore, a myriad of studies
have been focused on the identification of extracellular factors in the
CNS that limit the axon growth after injury. In this regard, three classes of
inhibitors have been characterized: members of classical repulsive guidance
cues such as semaphorins, ephrins, netrins; myelin-associated inhibitors such
as Nogo, Myelin-associated glycoprotein (MAG), oligodendrocyte myelin
glycoprotein; and glial scar-derived chondroitin sulfate proteoglycans
(CSPGs) (
Giger, Hollis, & Tuszynski, 2010
). Cell surface receptors that me-
diate the actionof regenerative inhibitors have been identified. For example, a
recent study suggested that the activation of epidermal growth factor receptor
is required for the activities of myelin inhibitors and CSPGs in limiting the
axon regeneration (
Koprivica et al., 2005
). Additional studies further revealed
paired immunoglobulin-like receptor B (PirB) and protein tyrosine phospha-
tase sigma (PTPsigma) as novel receptors for myelin- and CSPGs-associated
inhibitors, respectively (
Atwal et al., 2008; Shen et al., 2009
).
However, genetic ablation or pharmacological inhibition of these extra-
cellular inhibitors only permits limited sprouting rather than sustained axon
