Biology Reference
In-Depth Information
SOCS3 is a negative regulator of the JAK/STAT pathway (Janus kinase/
signal transducer and activator of transcription). Many cytokines signal
through the JAK/STAT pathway including interleukin-6, a cytokine
upregulated after conditioning lesionwhich has been linked to increased neu-
rite outgrowth and regeneration (
Cao et al., 2006
). STAT3 is itself associated
with increased neurite outgrowth in cultured cortical neurons (
Smith et al.,
2011
), including being one of the transcription factors upregulated in DRGs
after a conditioning lesion (
Qiu, Cafferty, McMahon, & Thompson, 2005
).
Likewise, deletion of STAT3 has been shown to impair peripheral nerve re-
generation (
Bareyre et al., 2011
). STAT3 is a critical mediator in SOCS3-
induced regeneration as it was determined that double deletion of STAT3
and SOCS3 abolishes regenerative growth observed with SOCS3 deletion
alone (
Sun et al., 2011
). In addition, studies involving the deletion of the
tumor suppressor gene PTEN in damaged CNS have yielded substantial re-
generation in both optic nerve and corticospinal axons (
Liu et al., 2010; Park
et al., 2008
). PTEN has several downstream effectors including mTOR
(mammalian target of rapamycin), GSK-3
b
(glycogen synthase kinase), and
3
0
-PIs (3
0
-phosphorylated phosphoinositides) (reviewed by
Liu et al.,
2011
).Developmentally,mTORactivity inRGCs and corticospinal neurons
are downregulated, with some data to suggest that protein levels (notmRNA)
are also decreased inDRGs (reviewed by
Liu et al., 2011; Xu, Zhao, Yaster, &
Tao, 2010
). Along with PTEN deletion-induced regenerative growth, the
ribosomal protein S6 kinase-1 was upregulated in RGCs, suggesting in-
creased activity in the mTOR pathway. Addition of rapamycin effectively
reduced phospho-S6-kinase-1 upregulation and suppressed regeneration
(
Park et al., 2008; Sun et al., 2011
). Dual deletion of SOCS3 and PTEN acts
synergistically to result in even better optic nerve regeneration than deletion
of either alone including significant amounts of regrowth when the deletion
of both genes was delayed after injury (
Sun et al., 2011
). This study also iden-
tified a large number of target genes regulated by SOCS3 and PTEN, includ-
ing regulators of neuronal transport and molecules involved with the
regulation of signaling through adhesion complexes.
3. AXONAL TRAFFICKING OF INTEGRINS AND OTHER
MEMBRANE PROTEINS
Growth-promoting integrins have the potential to stimulate regener-
ative axon growth (as discussed above); however, in order to function, they
must first be transported to the anterior tip of the damaged axon. At present,
