Biology Reference
In-Depth Information
proposed an alternative hypothesis, however, that the regenerative growth
seen through a PN graft was due to the secretion of trophic factors by
Schwann cells (
Berry, Carlile, & Hunter, 1996
). To test this idea, they
implanted a segment of PN into the posterior chamber of the eye and found
that this stimulated RGCs to regenerate lengthy axons through the optic
nerve itself (
Berry et al., 1996
). However, these grafts also contained numer-
ous inflammatory cells, and a few years later, we discovered that intraocular
inflammation alone, resulting either from lens injury or from injecting the
yeast cell wall preparation Zymosan into the eye, was sufficient to induce ex-
tensive optic nerve regeneration (
Leon, Yin, Nguyen, Irwin, & Benowitz,
2000
). This result has been repeated multiple times (
Lorber, Berry, &
Logan, 2005; Pernet & Di Polo, 2006; Yin et al., 2003
). Using
fluorescent-activated cell sorting to isolate RGCs followed by microarray
analysis, our lab reported that axotomy causes some changes in RGCs'
program of gene expression. However, when exposed to factors associated
with intraocular inflammation, the changes in RGC gene expression
become dramatic and include a massive upregulation of genes encoding
GAP-43, SPRR1, and many other proteins, in a pattern resembling that
seen in dorsal root ganglion neurons undergoing axon regeneration after
PN damage (
Fischer, Petkova, Thanos, & Benowitz, 2004
).
2. ONCOMODULIN PLAYS A CENTRAL ROLE IN
INFLAMMATION-INDUCED REGENERATION
These findings raise the question of how inflammation leads to axon
regeneration. Our early studies in cell culture showed that mannose, a simple
carbohydrate that is abundant in the eye, stimulates some outgrowth from
RGCs, provided intracellular levels of the second messenger cAMP are
elevated (
Li, Irwin, Yin, Lanser, & Benowitz, 2003
). However, neither
mannose nor elevated cAMP can account for the effects of inflammation
in switching RGCs into a robust growth state. Mannose is already abundant
in the eye and is therefore not limiting, and the addition of a cAMP analog
has only a minor effect
in vivo
(
Monsul et al., 2004; Yin et al., 2006
). Lens
injury or zymosan injections lead to a massive influx of neutrophils and
macrophages into the eye, suggesting that a factor derived from these
cells could be responsible for transforming RGCs into an active growth
state. We therefore collected media conditioned by a macrophage cell
line and discovered that it contained a low molecular weight protein that
enhanced the ability of RGCs
to extend axons
in the presence of
