Biology Reference
In-Depth Information
the myelin-associated inhibitors and CSPGs, most of the chemorepulsive
factors signal via Rho. Four classes of guidance molecules have been impli-
cated in inhibiting nerve regeneration: ephrins, netrins, semaphorins, and
repulsive guidance molecules (RGMs). Ephrins and their receptor Eph
tyrosine kinases are a family of guidance proteins capable of bidirectional
signaling between neurons and oligodendrocytes, and they are expressed
in injured spinal cord (
Bundesen, Scheel, Bregman, & Kromer, 2003;
Fabes et al., 2006; Miranda et al., 1999
). Ephrin-B3 is persistently
expressed in oligodendrocytes where it has strong axon growth inhibitory
activity (
Benson et al., 2005
). Netrin-1 is a bifunctional ligand that
can function as a chemoattractant or chemorepellent depending on
the receptor type it interacts with (
Moore, Tessier-Lavigne, & Kennedy,
2007
). Netrin-1 inhibits axon growth (
L¨w, Culbertson, Bradke, Tessier-
Lavigne, & Tuszynski, 2008
), and netrins affect Rho signaling
(
Moore et al., 2008
). The semaphorin family has both soluble and
transmembrane-bound members that mediate repulsion in development,
and these proteins are reexpressed in CNS injury (
Luo, Raible, & Raper,
1993; Pasterkamp & Verhaagen, 2006
). Sema4D is an oligodendrocyte
transmembrane protein that inhibits axon growth and is transiently
upregulated following CNS injury (
Moreau-Fauvarque et al., 2003
).
Sema3A is a soluble inhibitory protein associated with the glial scar (
De
Winter et al., 2002; Pasterkamp et al., 1999
), and Sema5A induces
growth cone collapse and inhibits retinal ganglion cell (RGC) outgrowth
from retinal explants; blocking Sema5A with a function-blocking
antibody neutralizes these effects (
Goldberg et al., 2004
). Semaphorins
inhibit axon growth via the activation of Rho (
Aurandt, Vikis, Gutkind,
Ahn, & Guan, 2002; Swiercz, Kuner, Behrens, & Offermanns, 2002
).
RGMa is also present in myelin and its expression increases at the lesion
site following SCI (
Hata et al., 2006
). RGMa inhibits axonal outgrowth,
and application of an RGMa function-blocking antibody promotes
regeneration. RGMa activates Rho in cerebellar neurons (
Hata et al.,
2006
). Therefore, Rho is important for signaling growth cone collapse
during axon guidance by the guidance-type axon growth inhibitors that
are expressed in the adult CNS following injury.
Together, it is clear that Rho is a converging molecule that mediates sig-
nals from all of the myelin-derived growth inhibitory proteins; fromCSPGs;
and from semaphorins, netrins, ephrins, and RGMs. Therefore, Rho is a key
target to promote regeneration in the injured CNS.
