Biology Reference
In-Depth Information
2001
).Mst3bmay play a homologous role inneurons, regulating aMAPkinase
pathway that leads to axon outgrowth in response to trophic factor signals
(
Lorber, Howe, Benowitz, & Irwin, 2009
). Activation of Mst3b using the pu-
rine nucleoside inosine induces the expression of growth-associated proteins
and axon outgrowth from RGCs of goldfish and zebrafish (
Petrausch et al.,
2000
).Deletionof thegeneencodingMst3bor expressinga dominant-negative
mutant form of the kinase prevents neurons from extending axons in response
to trophic factors, and conversely, expression of a constitutively active form of
Mst3b enables neurons to extend axons in the absence of trophic factors (
Irwin,
Li,O'Toole, &Benowitz, 2006; Lorber et al., 2009
).
In vivo
, suppressingMst3b
levels using AAV-mediated expression of an shRNA blocks inflammation-
induced regeneration of the optic nerve (
Lorber et al., 2009
).
4. SYNERGY BETWEEN ACTIVATING RGCS
'
INTRINSIC
GROWTH STATE AND COUNTERACTING CELL-
EXTRINSIC INHIBITORS OF GROWTH
The discovery that CNS neurons can regenerate axons through a PN
graft led to a search both for components of the CNS that are inhibitory to axon
growth and components of the PNS that are permissive to growth. This effort
has led to the discovery that multiple proteins associated with myelin, the peri-
neuronal net, and the glial scar that forms at the site of injury suppress axon
growth in the CNS; and that laminin and growth factors secreted by Schwann
cells facilitate axon growth in the PNS. In brief, major inhibitory factors asso-
ciated with CNS myelin include Nogo A and B, myelin-associated glycopro-
tein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), semaphorins, and
sulfatides, whereas major inhibitory factors associated with the perineuronal net
include chondroitin and keratin sulfate proteoglycans (CSPGs, KSPGs) and
particular ephrins (
Cafferty, McGee, & Strittmatter, 2008; Filbin, 2003;
Hannila, Siddiq, & Filbin, 2007; Kadoya et al., 2009; Liu, Cafferty, Budel, &
Strittmatter, 2006; Rossignol, Schwab, Schwartz, & Fehlings, 2007; Schwab,
2002; Silver & Miller, 2004
). The response of growth cones to these
inhibitors is mediated by diverse receptors, some of which are shared by
multiple ligands, while others are unique to particular ligands. Nogo A and
B, MAG, and OMgp all bind to particular isoforms of the Nogo receptor
and to PirB, although MAG acts through other receptors as well (
Atwal
et al., 2008; Filbin, 2003; Fournier, Gould, Liu, & Strittmatter, 2002;
Fournier, GrandPre, & Strittmatter, 2001; Goh et al., 2008; Schweigreiter
et al., 2004; Wang et al., 2002
). CSPGs and KSPGs likewise act through
multiple receptors, including protein tyrosine phosphatase receptor sigma
