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and Pten and Tsc2 (likely acting through mTOR inactivation) as negative
regulators of peripheral nerve regeneration.
Regeneration by the central projection of DRG neurons has also been
promoted by some gene manipulations. In mice that overexpress Gap-43
and Cap-23, both of which are upregulated by peripheral injury, central
DRG axons showed an improved ability to extend axons into peripheral
nerve grafts in the spinal cord (
Bomze, Bulsara, Iskandar, Caroni, & Skene,
2001
). Transducing DRG neurons with a constitutively active form of
CREB, a likely downstream effector of cAMP elevation and potential
mediator of the DRG cell body response to peripheral injury, also increased
DRG axon regeneration into sites of spinal injury (
Gao et al., 2004
).
Retinoic acid signaling accompanies peripheral nerve injury, and viral
delivery of retinoic acid receptor
b
2 to adult DRGs improved regrowth
of injured axons across the dorsal root entry zone and into the spinal cord
(
Wong et al., 2006
). Overexpression of the transcriptional regulator Id2 also
modestly improved the ability of central DRG axons to regenerate into sites
of spinal injury (
Yu et al., 2011
). However, overexpression of Atf3 or Stat3,
which are strongly upregulated and activated by peripheral injury, produced
small (Stat3) or no (Atf3) improvements in central regeneration by DRG
neurons (
Bareyre et al., 2011; Seijffers et al., 2007
). Thus, altering the
expression of individual genes in DRG neurons to mimic the effect of
peripheral injury is sufficient in some cases, but not all, to promote
regeneration in the spinal cord.
In CNS neurons, overexpression of PNS-enriched genes has had simi-
larly mixed success in promoting regeneration. Overexpression of Gap-43
does not increase regeneration by thalamocortical neurons, but combined
overexpression of Gap-43 and the adhesion molecule L1 modestly increases
the regeneration of Purkinje cell axons into peripheral nerve grafts (
Mason,
Campbell, Caroni, Anderson, & Lieberman, 2000; Zhang et al., 2005
). Viral
delivery of receptor retinoic acid receptor
b
2 to CST neurons enhanced
axon counts below the site of a spinal injury (
Yip et al., 2006
). The use
of a dorsal crush model in this study, which spares the ventral and lateral
CST, makes it difficult to distinguish regeneration from the sprouting of
spared fibers. Viral transduction of CST neurons with the BDNF
receptor TrkB, which is upregulated by some regenerating PNS neurons,
was recently shown to increase axon growth after subcortical
injury
(
Hollis, Jamshidi, Low, Blesch, & Tuszynski, 2009
).
Socs3, a negative regulator of cytokine signaling, is a notable success story
in using PNS research to guide the promotion of CNS regeneration. Socs3
