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gene targets of relevance to adult CNS regeneration. Interestingly, in the
case of Klf7 in CST neurons, wild-type Klf7 proved ineffective in pro-
moting regeneration due to low expression
in vivo
. To circumvent this
limitation, the endogenous activation domain was replaced by the viral
VP16 activation domain, which displayed higher expression and effective
transcriptional activation and growth promotion. Thus, the initial screens
were effective in flagging an important set of regulatory factors, but due
to complex regulation, simple manipulation of gene expression was not
enough to promote axon regeneration
in vivo
. This example highlights
the need to follow screens with targeted experiments to clarify and
manipulate accessory regulatory mechanisms. Overall, however, these
experiments demonstrate the power of large-scale comparisons of imma-
ture, regeneration-competent neurons to their mature counterparts to
identify important growth-regulatory proteins, thereby launching the
development of novel tools to promote CNS regeneration.
3. COMPARISONS ACROSS SPECIES
3.1. Correlative and functional tests of gene function
Invertebrate species, including leech,
Caenorhabditis elegans
, and Drosophila,
are generally capable of axonal regeneration, with some variability across cell
type and age (
Gabel, Antoine, Chuang, Samuel, & Chang, 2008; Mladinic,
Muller, & Nicholls, 2009; Wu et al., 2007; Yanik et al., 2004
). Similarly,
some nonmammalian vertebrates display successful axon regeneration in
CNS populations; RGCs and a subset of supraspinal populations in fish
and amphibians are prominent examples (
Becker & Becker, 2008;
Becker, Wullimann, Becker, Bernhardt, & Schachner, 1997; Lurie &
Selzer, 1991
). In contrast to the cellular atrophy often observed after
axotomy of mammalian CNS neurons, RGCs in teleost fish respond to
axotomy by long-lasting increases in cell size and sprouting of new
processes near the cell body, underscoring cross-species differences in the
cell body response to axotomy (
Becker & Cook, 1990; Burmeister &
Grafstein, 1985; Egan, Flumerfelt, & Gwyn, 1977; Kobayashi et al., 1997;
Moore & Thanos, 1996
).
Similar to the developmental studies described earlier, genes linked to
successful axon regeneration in nonmammalian species span diverse func-
tional categories. In regenerating teleost fish axons, genes correlated with
CNS regeneration include adhesive receptors (integrins, various IgG super-
family members, cadherins),
structural proteins
(tubulin isoforms and
