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RGCs of trk receptors ( Cui, Tang, Hu, So, & Yip, 2002; Hirsch, Labes, &
B¨hr, 2000 ) and neurotrophin (BDNF) expression ( Gao, Qiao, Hefti,
Hollyfield, & Knusel, 1997; Hirsch et al., 2000 ), and altered mRNA
expression for GDNF and cognate receptors GFRalpha1 and 2, and Ret
( Lindqvist, Peinado-Ramonn, Vidal-Sanz, & Hallbook, 2004 ). FGF2 and
FGFR1 are increased in photoreceptors 21-28 days after ON crush ( Valter
et al., 2005 ). HGF levels have not been measured but expression of its
receptor cMet increases in RGCs as early as 6 h after ON injury ( Tonges,
Ostendorf, et al., 2011 ).
Yet, despite the presence of intrinsically and extrinsically derived neuro-
trophic factors, at least some of which are potentially beneficial, expression
of these various factors is not sufficient to maintain adult RGCs and initiate
regenerative axonal responses after disconnection from visual centers in the
brain. There is some evidence that any impact of endogenous, retinally
derived trophic factors is offset by other signaling systems in injured RGCs.
For example, in an ocular hypertension model, antagonists of the leucine-
rich repeat and Ig domain containing Nogo receptor-interacting protein-1
(LINGO-1), an essential component of the Nogo receptor complex, not
only enhance the RGC survival effects of exogenously applied BDNF
( Fu et al., 2009 ) but also enhance the impact of endogenously expressed
BDNF ( Fu et al., 2010 ). In the latter case, the authors show that
LINGO-1 complexes with, and negatively regulates, trkB; LINGO-1
antagonists increase trkB phosphorylation in RGCs leading to increased
BDNF-driven survival of these neurons. Similarly, expression of the nega-
tive suppressor of cytokine signaling (SOCS) 3 in RGCs ( Hellstr ¨ m,
Muhling, et al., 2011; Smith et al., 2009 ) reduces any impact of retinally
derived cytokines such as CNTF and LIF on RGC survival and axonal
regeneration after injury.
Thus, without external intervention, ON transection in adult rats leads
to RGC death that begins about 4 days after the injury, with at least 90% of
the RGC population lost by 14 days. RGC loss is most rapid when injuries
are made proximally, and is slower after ON crush (reviewed in Harvey
et al., 2006 ). There is little in the way of spontaneous regeneration of axons
from the fraction of RGCs that survive ON injury, although some slow
regrowth of small caliber axons has been reported ( Campbell et al.,
1999 ). In addition, at least some adult RGC axons can regenerate for
5-6 mm in glial-connective tissue membranes that form over lesion sites af-
ter adult optic tract injury and these axons retain the selective ability to
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