Biology Reference
In-Depth Information
2.2.4 Modulation of PTEN/mTOR and desensitization to MAG/CSPGs
Axon regeneration failure in the CNS can be partly explained by numerous
inhibitory environmental cues present at the lesion site that chemically impede
axon growth. Of these, the myelin-associated inhibitors (MAI; e.g., nogo,
MAG and OMgp) and CSPGs have been studied most extensively. It is
known that CNS neurons express various MAG receptors including the Nogo
receptors (NgR1 and NgR2) (
Domeniconi et al., 2002; Liu, Fournier,
GrandPre, & Strittmatter, 2002; Venkatesh et al., 2005
), gangliosides
GD1a, GT1b (
Yang et al., 1996
)(
Vinson et al., 2001; Vyas et al., 2002
),
and paired immunoglobulin-like receptor B (PirB) (
Atwal et al., 2008
).
CSPG receptors expressed by CNS neurons identified so far are protein
tyrosine phosphatase
s
,NgR1andNgR3(
Dickendesher et al., 2012; Shen
et al., 2009
). Binding of these receptors to MAIs or CSPGs triggers
intracellular signaling leading to RhoA/ROCK activation and growth cone
collapse (
Hall & Lalli, 2010; Monnier, Sierra, Schwab, Henke-Fahle, &
Mueller, 2003; Niederost, Oertle, Fritsche, McKinney, & Bandtlow, 2002
).
Studies have demonstrated that depletion of PTEN in neurons confers
axons with the ability to overcome these growth-inhibitory factors. In the
optic nerve, CSPGs accumulate at the lesion site within 1 day after crush
injury, and persist for several days (
Park et al., 2008; Selles-Navarro,
Ellezam, Fajardo, Latour, & McKerracher, 2001
). While RGC axons in
wild-type animals are mostly unable to grow into the lesion site in the
optic nerve, axons of PTEN-deleted RGCs show enhanced growth into
the CSPG-rich lesion site shortly after injury.
In vitro
inactivation of PTEN
in dissociated cortical neurons increased neurite outgrowth over MAG
(
Perdigoto et al., 2011
) whereas inhibition of mTOR activity reduced
neurite outgrowth of cultured RGCs on myelin or CSPGs (
Leibinger
et al., 2012
). Thus, these studies indicate that PTEN has a role in the
growth cone collapse in response to MAG, whereas mTOR activity is
important to overcome the inhibitory effects of myelin and CSPGs. What
are the intracellular mechanisms by which inactivation of PTEN
desensitizes axons to these inhibitory substrate components? Similar to the
effects seen after PTEN inactivation, expression of constitutively active
AKT in cortical neurons is sufficient to reverse the inhibition of neurite
outgrowth by MAG, suggesting that AKT may act downstream to PTEN
in overcoming MAG inhibition. Further, it was shown that MAG reduces
AKT phosphorylation in cortical neurons
in vitro
(
Perdigoto et al., 2011
).
Suppression of AKT activity would increase the activation of GSK3 and
impair growth cone formation (as described in
Section 2.2.3
). PTEN has
