Biology Reference
In-Depth Information
preconditioned neurons (
Christie, Webber, Martinez, Singh, & Zochodne,
2010
). Further,
in vivo
regeneration following severe sciatic nerve injuries
was accelerated after local inhibition of PTEN at the injury site. Thus, while
previous studies showed enhanced axon regeneration after neuron-specific
suppression of PTEN (
Liu et al., 2010; Park et al., 2008; Sun et al., 2011
),
axon regeneration seen after local inhibition of PTEN at the lesion site
(
Christie et al., 2010
) raises the possibility that inactivation of PTEN in
neighboring cells (including PTEN-expressing Schwann cells) may have
contributed to the enhanced axon regrowth in the PNS. Overall, these
findings clearly demonstrated that PTEN has a role in limiting axon
regeneration, and relieving its actions on neurons permit enhanced axon
growth. One important question remains: how does inactivation of PTEN
increases axon growth potential?
2.2. Downstream effectors of PTEN
2.2.1 PI3K/AKT
There has been a surge of new information in the past several years con-
cerning how the PI3K/AKT signal might be conveyed to its downstream
targets to regulate different steps of axon growth from initial axon formation
to axon extension. This pathway has been shown to influence many features
of axon growth including axon elongation, branching, caliber, growth cone
assembly and polarity. Such different functions are likely to be mediated by
different downstream effectors of this pathway. Given the negative role of
PTEN on activation of PI3K/AKT, axon regeneration induced after PTEN
inactivation could be explained partially by downstream activation of PI3K/
AKT signaling. In support of this, PTEN inactivation leading to increased
AKT activity or direct overexpression of activated AKT is sufficient to
increase neurite outgrowth
in vitro
(
Perdigoto et al., 2011
). However,
whether or not overexpression of active AKT in different neuronal cell
types could enhance
in vivo
axon regeneration is less clear. Also, direct ev-
idenceoftheinvolvementofAKTactivationonaxonregenerationinthe
background of PTEN deletion is lacking. Recently, AAV-expressing con-
stitutively active AKT induced robust regrowth of axons from dopaminer-
gic neurons after axon lesion induced by a neurotoxin. Moreover, this
treatment led to target reinnervation and partial behavioral recovery
(
Kim,Chen,etal.,2011
). Of note, axon damage resulting from a neuro-
toxin is progressive and does not produce disruption of brain parenchyma
(i.e., absence of glial scar and myelin disruption). Nonetheless, it seems that
at least for certain CNS neurons, forced AKT activation is sufficient to
