Biology Reference
In-Depth Information
First, by forcing expression of an integrin matched to the available ligands, it
is possible to enhance axon regeneration. Second, integrin-mediated axon
growth is relatively well understood, so by finding out where there are de-
fects in the pathway, fundamental issues affecting the failure of axon growth
can be discovered. Expression of an integrin that interacts with available
molecules in the ECM has the potential to change the intrinsic growth abil-
ity of an axon, as expression of a single subunit of a growth-promoting
integrin can allow for growth in an otherwise inhibitory environment.
Thus, expression of
a
9 integrin allows for axon growth over tenascin-C
(a glycoprotein that is upregulated after CNS injury)
in vitro
and some
sensory axon regeneration into the spinal cord
in vivo
(
Andrews et al., 2009
).
Integrins are complex receptors in that they function bidirectionally, with
the affinity for their ligands being strictly regulated by activation in an inside-
out fashion, while binding of activated integrins to their ligands leads to
outside-in signaling (
Hynes, 2002
). Additionally, their correct localization
to specific parts of the surface membrane is crucial. This is tightly controlled
by internalization, intracellular trafficking, and recycling onto the cell surface
(
Caswell, Vadrevu, & Norman, 2009
). Activation, trafficking, and transport
are all involved in the effects of
a
9 integrin expression on axon growth; var-
iations in these functions explain why expression of the integrin allows more
growth
in vitro
than
in vivo
in the spinal cord. We and others have found that
inhibitory molecules in the CNS can inactivate integrins (
Hu & Strittmatter,
2008; Tan et al., 2011
), and that they can regulate integrin expression on the
growth cone surface (
Hines, Abu-Rub, &Henley, 2010
), but we also observe
that integrin transport into some CNS axons
in vivo
is limited (Melissa
Andrews, Sara Soleman, Chin-Lik Tan, Joost Verhaagen, James Fawcett,
unpublished results). This is similar to the finding that exogenously expressed
tyrosine kinase (Trk)B is not fully transported into corticospinal axons in the
spinal cord (
Hollis, Jamshidi, Low, Blesch, & Tuszynski, 2009
).
1.2. Integrin function
Integrins are heterodimeric proteins consisting of an
a
and a
b
subunit. The
combination of these subunits governs the specificity of their binding to the
ECM. At present, 18
a
and 8
b
subunits have been identified. These subunits
combine to generate 24 heterodimers which bind with different affinities to
ECM molecules such as fibronectin, collagen, laminin, tenascin, and
vitronectin (
Hynes, 2002; Myers et al., 2011
). The affinity of the assembled
dimers for their ligands is regulated by activation from the inside-out. This is
