Biology Reference
In-Depth Information
regulates the activity of transcription factors by modifying chromatin
structure and DNA binding site accessibility. P300 is downregulated
during RGC development, and overexpression of this protein promotes
RGC regeneration by driving expression of several genes including
GAP-43. Thus, p300 targets both the epigenome and transcription to
activate a “postinjury silent gene expression program” that supports
axonal regeneration (
Gaub et al., 2011
). The potential for using this and
other epigenetic regulators to induce proregenerative responses in injured
neurons has been the subject of a recent
review (
Trakhtenberg &
Goldberg, 2012
)
In addition to the intrinsic limitation on regenerative capacity, RGC
axons are strongly inhibited by the environment of the adult brain,
effects that can be further exacerbated following injury. Many of these ex-
trinsic factors have been characterized. In brief, oligodendrocyte-derived
proteins such as myelin-associated glycoprotein (MAG), Nogo-A, and
oligodendrocyte-myelin glycoprotein elicit growth cone collapse in RGCs
(
McKerracher & Winton, 2002
). Nogo-A binds to the Nogo Receptor
(NgR1), and signal transduction requires the formation of a receptor com-
plex that includes p75 and LINGO-1 or TROY, an orphan receptor of the
TNF receptor superfamily. Other potentially inhibitory factors include
chondroitin sulfate proteoglycans (CSPGs) and tenascin-C, extracellular
molecules that are produced by reactive ON glia and meningeal cells
(
Hirsch & B
¨
hr, 1999
), and members of the semaphorin family (
de Winter,
Cui, Symons, Verhaagen, & Harvey, 2004
). Myelin-associated and CSPG
growth-inhibitory factors act on neurons by converging on the Rho/
Rho kinase (ROCK) pathway to modify actin dynamics and trigger growth
cone collapse (e.g.,
Berry et al., 2008; Tonges, Koch, B¨hr, & Lingor, 2011
).
PTEN is activated by ROCK (
Li et al., 2005
) as is the collapsin response
mediator protein 2 (CRMP2), which is also in the PTEN pathway
(
Yoneda, Morgan-Fisher, Wait, Couchman, & Wewer, 2012
). PTEN
signaling is implicated in the myelin inhibitory signaling pathway
(
Alabed, Pool, Ong Tone, Sutherland, & Fournier, 2010
), and
prevention of Nogo-A initiated phosphorylation of CRMP2 all but stops
RGC axonal degeneration after demyelinating ON injury (
Petratos et al.,
2012
). Importantly, inhibition of Rho or ROCK enhances regrowth of a
proportion of RGC axons across an ON crush (e.g.,
Bertrand, Winton,
Rodriguez-Hernandez, Campenot, & McKerracher, 2005; Fischer,
Petkova, Thanos, & Benowitz, 2004; Hu, Cui, & Harvey, 2007; Lingor
et al., 2008
).
