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growth, and inhibitors of the JAK pathway block only regenerative growth
( Liu & Snider, 2001 ). Furthermore, DRG neurons show age-dependent
differences in sensitivity to actin-depolymerizing drugs, such that axon
growth by older neurons proceeds by an actin-dependent mechanism
( Jones, Selzer, & Gallo, 2006 ). These results are somewhat unexpected
because prominent models of axon extension, built on observations in
embryonic neurons and immature invertebrate neurons in culture, assign
a central role to actin dynamics and actin-mediated linkage to the
substrate (i.e., the “clutch hypothesis”) ( Suter & Forscher, 2000 ). The
finding that actin may be dispensable for axon growth in some
regenerating adult neurons hints at a different mechanism of extension at
the level of the cytoskeleton. Similarly, numerous differences in gene
expression between regenerative and developmental axon growth have
also been noted, involving for instance the set of tubulin- and
microtubule-associated protein isoforms ( Fawcett, Mathews, Housden,
Goedert, & Matus, 1994; Halverson, Chambers, & Muma, 2001; Ma,
Connors, Nothias, & Fischer, 2000; Woodhams, Calvert, & Dunnett,
1989 ). Finally, even in cases where developing and regenerating neurons
express identical genes (for instance, Gap43 or tubulin alpha 1), different
promoter regions are utilized, suggesting differences in underlying
transcriptional control ( Udvadia, Koster, & Skene, 2001; Veldman et al.,
2010 ). Thus, clarifying the molecular details of how PNS neurons mount
an effective regenerative response will likely provide insights into axon
growth that are nonidentical and perhaps complementary to the
developmental studies discussed earlier.
A sizable literature has functionally tested putative PNS regenerative
genes in vivo . These experiments can be divided conceptually into two cat-
egories: those that test whether a given gene is necessary for successful re-
generation and those that test whether a given gene is sufficient to enhance
regeneration. To test necessity, candidate genes are targeted by transgenic
deletion, siRNA, or dominant negative blockade, and then animals are
tested for resulting defects in PNS regeneration. Knockout of the adhesion
receptor alpha7 integrin ( Werner et al., 2000 ), the intermediate filament
vimentin ( Perlson et al., 2005 ), the peptide galanin ( Holmes et al.,
2000 ), or overexpression of a truncated form of Gap-43 that is dominant
negative with respect to the assembly of plasma microdomains ( Laux et al.,
2000 ) all have the effect of delaying, but not preventing regeneration in the
periphery. Mice that lack p21 Cip1/Waf1 showed delayed functional recovery
after sciatic nerve crush, but
this effect
likely resulted from slowed
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