Biology Reference
In-Depth Information
which a PN graft is sutured to the cut end of the optic nerve, CNTF was
found to increase the levels of Socs1, -2, and -3 mRNA and protein in
the retina, although the addition of a cAMP analog diminished this effect
(
Park et al., 2009
). One group reported positive effects of CNTF in this same
model but found that this was due to CNTF acting as a chemoattractant for
macrophages (
Cen et al., 2007
). Another group reported effects of
CNTF in cell culture that required concentrations 2-3 orders or magnitude
above the known EC
50
, and reported effects of high concentrations
in vivo
without investigating whether this might have been an indirect effect of
acute inflammation (
Leibinger et al., 2009; Muller, Hauk, & Fischer,
2007
). However, CNTF and the related cytokine LIF may be important
for RGC survival, as deletion of the genes encoding both of these
simultaneously diminishes RGC survival and axon regeneration after
nerve injury (
Leibinger et al., 2009
).
Altering the expression of transcription factors provides another way to
affect RGCs' intrinsic growth state and promote regeneration (reviewed by
Liu, Tedeschi, Park, & He, 2011; Moore & Goldberg, 2011
). As noted
earlier, RGCs switch from a state of rapid axon outgrowth to a dendritic
growth state in the early postnatal period as a result of contact with
amacrine cells (
Goldberg et al., 2002
). This switch is associated with
dramatic changes in RGCs' program of gene expression, including
the upregulation of KLF4 and certain other KLF family transcription
factors that suppress axon growth; at the same time, RGCs show a
downregulation of KLF6 and 7, members of the same family that promote
axon outgrowth (
Goldberg et al., 2002; Veldman, Bemben, & Goldman,
2010; Veldman, Bemben, Thompson, & Goldman, 2007
). Deleting the
gene that encodes the suppressive transcription factor KLF4 stimulates a
moderate level of optic nerve regeneration in mice (
Moore et al., 2009
).
Another way to activate pro-regenerative transcriptional machinery of
RGCs has been to overexpress the acetyltransferase p300. p300
overexpression increases histone acetylation, acetylation of the transcription
factors p53 and C/EBP, and expression of GAP-43 and other growth-
associated gene products. These changes are accompanied by a modest
increase in optic nerve regeneration (
Gaub et al., 2011
).
Another molecule involved in regulating axon growth is the purine-
sensitive protein kinase Mst3b. Mst3b is a neuron-specific homolog of
Ste20, a protein kinase that acts as an upstream activator of theMAP kinase sig-
naling pathway that controls budding in yeast (
Dan, Watanabe, & Kusumi,
