Biology Reference
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observations; Erich Ehlert and Joost Verhaagen, personal communication;
Hollis et al., 2009
). Additionally, we examined whether forced activation of
integrins would lead tomore substantial regeneration especially in the presence
of Nogo-A and CSPGs (both highly upregulated in CNS lesions), as these are
known to inactivate integrins (
Hu & Strittmatter, 2008; Tan et al., 2011
).
Activating integrins with cation treatment or with
b
1-integrin-activating
antibodies has shown promise as either treatment promotes outgrowth in
the presence of CSPGs and Nogo-A (
Tan et al., 2011
). Intracellularly, the
integrin-regulatory proteins kindlin-1 and -2 have been shown to enhance
the activation state of integrins via binding the
b
integrin subunit and inducing
downstream signaling events (
Moser, Nieswandt, Ussar, Pozgajova, & Fassler,
2008
). Expression of kindlin-1 (absent in CNS neurons) in DRG neurons en-
hances neurite outgrowth in the presence of the CSPG aggrecan with
corresponding increase in phosphorylation of the downstream signaling mol-
ecule FAK. In addition, kindlin-1 overexpression
in vivo
promotes sensory
axon regeneration after dorsal root crush with axons extending through the
dorsal root entry zone and into the dorsal columns (
Tan et al., 2012
).
Regenerative growth with kindlin-1 overexpression was observed at further
distances in the spinal cord than with
a
9 integrin overexpression likely due to
the ability of kindlin-1 to activate several integrins, rather than one specific
heterodimer. Further studies are required to investigate kindlin-1 over-
expression in CNS neurons. Interestingly, although overexpression of
integrins or increasing cAMP levels have been shown to significantly increase
neurite outgrowth, stimulation of the two molecules together induces growth
cone collapse. Both pathways alone function to stimulate Rac activation lead-
ing to growth cone motility and neurite outgrowth; however, both together
have a detrimental result on growth cone dynamics suggesting a balance be-
tween the two is necessary for efficient and coordinated outgrowth (
Lemons &
Condic, 2006
). The relationship between integrins and cAMP remains unclear
however, as not only has integrin activation been shown to suppress cAMP
levels (
Lemons & Condic, 2006
) but also cAMP has been shown to mediate
integrin-mediated cell adhesion through the Epac-Rac1 pathway in
nonneuronal cells (
Rangarajan et al., 2003
).
2.3. SOCS3 and PTEN
Perhaps, the most potent strategy for enhancing intrinsic regeneration has
come from studies of two molecules, SOCS3 and PTEN. Deletion of
SOCS3 (suppressor of cytokine signaling 3) in adult retinal ganglion cells
has shown promising results in optic nerve regeneration (
Smith et al., 2009
).
