Biology Reference
In-Depth Information
First, the activity of mTOR pathway is developmentally downregulated in
the CNS neurons as reflected by reduced phosphorylation level of its down-
stream effector ribosomal protein S6. Second, the low level of mTOR ac-
tivity is further decreased by axotomy-triggered stress response, thus
rendering limited capacity of new protein synthesis that is required for axon
regeneration. Third, inhibition of mTOR activity by rapamycin administra-
tion abrogates the regenerative response in PTEN-deleted optic neurons
after axonal injury (
Park et al., 2008
). In addition to PTEN deletion, genetic
ablation of another negative regulator of mTOR, tuberous sclerosis protein
1 (TSC1), also enhances the regenerative ability. However, the regenerative
effect is not as robust as PTEN deficiency. Although the pathways mediating
axotomy-induced mTOR suppression remain unclear, present findings
suggest that elevating mTOR promotes the axon regeneration through
S6K1-mediated protein synthesis.
Interestingly, Cdk5 has been suggested to regulate mTOR signaling by
facilitating mTOR-dependent activation of S6K1. Prior to activation, S6K1
exists in an autoinhibited form and priming phosphorylation of multiple
Ser/Thr sites in the autoinhibitory domain is required for S6K1 activation
by mTOR. Among these Ser/Thr residues, Ser411 is conserved across
several species, and is required for S6K1 activation (
Schalm, Tee, & Blenis,
2005
). It has been suggested that Cdk5 is responsible for the phosphorylation
of S6K1 at Ser411 in the nervous system (
Hou, He, & Qi, 2007
). These
results suggest a molecular mechanism by which Cdk5 regulates axon
growth through S6K1-mediated protein synthesis. However, whether
Cdk5-dependent Ser411 phosphorylation of S6K1 is involved in mTOR-
dependent axon regeneration awaits further characterization.
2.4.2 eIF-4E and local protein translation
Aside from global translation, local protein synthesis within specific cellular
compartments, such as growth cones or axon shafts, is also essential for various
aspects of axon development, including axon navigation and maintenance.
On one hand, due to the relative long distance away from the cell body, axon
utilizes local mRNA translation to respond to guidance cues, such as
semaphorin 3A. On the other hand, intra-axonal translation is required for
maintenance of axon shafts, since loss of axonal components, such as axonally
synthesized intermediate filament lamin B2, results in axon degeneration
(
Yoon et al., 2012
). In addition, local protein translation is necessary for
efficient growth cone regeneration after axotomy (
Verma et al., 2005
).
