Biology Reference
In-Depth Information
innervate appropriate target regions in fetal SC grafted into the lesion site
(
Harvey & Tan, 1992
).
4. RECEPTORS AND MISCELLANEOUS SIGNALING
PATHWAYS THAT INFLUENCE AXONAL
REGENERATION
Although this review is focused on neurotrophic factors, the reader
should keep in mind that any axogenic effects elicited in injured adult RGCs
by these factors should be integrated into what is known about the intracel-
lular signaling pathways that need to be either activated or inactivated to
overcome intrinsic (
Moore, Apara, & Goldberg, 2011; Sun & He, 2010
)
or extrinsic (
Berry et al., 2008
) restrictions on axonal growth. Any impact
of endogenous, retinally derived trophic factors is likely to be offset
by other signaling systems in injured RGCs. Over the past two decades,
numerous excellent studies have revealed some of the important
players that compromise axogenesis in adult RGCs after ON crush or
transection. Increasingly, these studies are being carried out in mice due
to the availability of transgenic lines that allow conditional deletion of
specific genes.
The protein PTEN (phosphatase and tensin homologue) has a repressive
effect on neurite outgrowth, and in transgenic mice, PTEN deletion pro-
motes regenerative growth of some RGC axons after ON crush
(
Kurimoto et al., 2010; Park, Liu, Hu, Kanter, & He, 2010; Park et al.,
2008
). The downstream mechanisms whereby PTEN deletion promotes
axonal regrowth are well characterized: PTEN deletion activates the
PI3K/mTOR (mammalian target of rapamycin) pathway, which controls
cell growth and size by regulating protein translation initiation. However,
other downstream targets of PTEN, such as Akt and GSK-3, may also
contribute to regenerative growth (
Park et al., 2008
). Similarly, a family
of transcription factors, Kruppel-like factors (KLFs), that are associated
with the developmental loss of intrinsic regenerative capacity (
Goldberg,
Klassen, Hua, & Barres, 2002
), have various influences on adult RGCs.
Knockout of the KLF4 family member during development increases the
regenerative potential of adult RGCs, whereas overexpression
in vitro
slows RGC neurite outgrowth by up to 50% (
Moore et al., 2011
).
Insight into how such genes might themselves be regulated comes from
studies of,
for example,
the histone acetyltransferase p300, which
