Biology Reference
In-Depth Information
activity in RGCs declines progressively during development (
Park et al.,
2008
); however, by adulthood, only a small population of total RGCs
(5-10%) retains mTOR activity (
Leibinger, Andreadaki, & Fischer,
2012; Park et al., 2008
), which correlates with the loss of regenerative
capacity of mature RGCs. Axon injury to adult RGCs, however,
triggers further decline of mTOR activity (
Leibinger et al., 2012; Park
et al., 2008
),whereasPTENdeletioninRGCspreventsthisaxotomy-
induced mTOR suppression (
Park et al., 2008
). It is unclear why and
how the mTOR activity is retained in only a small subset of adult
RGCs, and what signal causes its suppression in the injured neurons.
Systemic application of rapamycin, a potent mTOR inhibitor in
PTEN-deleted animals resulted in significant reduction in optic axon
regeneration (
Park et al., 2008
), pointing to a pivotal role for mTOR
activation on axon regeneration in the background PTEN deletion.
Similarly, PTEN depletion in purified motor neurons using siRNAs
promoted significant axon growth, an effect that was inhibited by
rapamycin treatment (
Ning et al., 2010
). On the contrary, in the PNS,
increased neurite outgrowth from DRG neurons after PTEN
inactivation was not affected by pharmacological inhibition of mTOR.
More direct approaches to activate mTOR were also shown to promote
axon regeneration: RGC-specific deletion of TSC1, a direct negative
regulator of mTOR (
Fig. 7.1
) also prevented axotomy-induced
suppression of mTOR activity and promoted regeneration of injured
RGC axons (
Park et al., 2008
). Similarly, viral-mediated overexpression
of Rheb, a direct activator of mTOR (
Fig. 7.1
), promoted extensive
axon regeneration of dopaminergic neurons (
Kim, Chen, et al., 2011
).
In the PNS, forced mTOR activation in DRG neurons by Advilin-Cre
mediated deletion of TSC2 was sufficient to enhance axon/neurite
growth both
in vivo
and
in vitro
in the absence of preconditioning
injury. Collectively, these studies indicate that forcing mTOR
activation facilitates the regenerative response in several types of CNS
and PNS neurons. Others have suggested the potential role of mTOR
in facilitating different features of axon growth: axon initiation and
axon elongation.
In the visual system, inflammatory stimulation (i.e., penetrating lens
injury) in the eye stimulates axon regeneration in the injured optic nerve.
Inactivation of mTOR decreased the number of axons regenerating over
long distances, without inhibiting the initial switch of RGCs into the regen-
erative state (i.e., did not decrease the number of axons regenerating short
