Biology Reference
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distances) (
Leibinger et al., 2012
), suggesting that activation of mTOR has a
more prominent role in supporting the elongation of regenerating axons
than triggering the initial growth.
How could mTOR facilitate axon regeneration? The two best character-
ized downstream targets of mTOR are S6K1 (p70-S6 Kinase 1) and 4E-BP1
(the eukaryotic initiation factor 4E (eIF4E) binding protein 1). Phosphoryla-
tion of S6K1 by mTOR leads to activation and consequent phosphorylation
of rS6 (ribosomal S6). This causes increased translation of mRNAs containing
a5
0
tract of oligopyrimidine that encode components of the translation appa-
ratus including ribosomal proteins and elongation factors (
Dobashi,
Watanabe, Miwa, Suzuki, & Koyama, 2011; Huang & Manning, 2009;
Proud, 2007, 2009
). Nonphosphorylated 4E-BP1 binds to the translation
initiation factor eIF4E, preventing it from binding to 5
0
-capped mRNAs
and recruiting them to the ribosomal initiation complex (
Fig. 7.1
). mTOR
phosphorylation of 4E-BP1 releases eIF4E, allowing it to initiate cap-
dependent translation (
Proud, 2007, 2009
). Overall, activation of mTOR
by various external stimuli (i.e., growth factors, nutrients, and hormones)
positively controls protein synthesis and cell growth by enhancing the
cellular capacity for ribosome biogenesis, translation initiation, and
elongation. Injury to the axons of central neurons (e.g., RGCs and CST
neurons) was shown to suppress protein synthesis and mTOR activity at
the cell body level (
Leibinger et al., 2012; Liu et al., 2010; Park et al.,
2008
). In contrast, axon injury to the peripheral neurons (e.g., DRG
neurons) triggers increase in the level of neuronal mTOR activation (
Abe,
Borson, Gambello, Wang, & Cavalli, 2010
). What accounts for this
profound disparity in injury response between these neurons is unknown,
but it may reflect differential regulation of cytokine, hormone, and growth
factor receptor expression in these neurons after injury. Enhanced axon
regeneration seen after mTOR activation in injured neurons could be
ascribed partially to increased capacity of neurons to synthesize
de novo
proteins required for the building blocks of newly extending axons. Several
studies have indicated that local protein synthesis at the axon level is critical
for the formation of growth cones in response to axotomy. Using
in vitro
outgrowth assays,
Verma et al. (2005)
demonstrated that protein synthesis
inhibitors (e.g., cyclohexamide) or rapamycin impairs formation of the
growth cone in embryonic sensory axons. As formation of a growth cone
is a prerequisite for axon regeneration (
Bradke, Fawcett, & Spira, 2012
),
protein synthesis in a cut axon that facilitates growth cone formation is
likely an integral component of axon regeneration for sensory axons.
