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The Journal of Neuroscience, September 1, 2000, 20(17):6551-6560
Regulation of Neurite Outgrowth by Integrin Activation
Jonathan K.
Ivins1,
Peter D.
Yurchenco2, and
Arthur D.
Lander1
1 Department of Developmental and Cell Biology and the
Developmental Biology Center, University of California at Irvine,
Irvine, California 92697, and 2 Department of Pathology and
Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway,
New Jersey 08854
During late-embryonic development, retinal neurons lose the ability
to attach and extend neurites on the extracellular matrix molecule laminin-1 (LN-1), despite the fact that they retain expression of integrin receptors for LN-1. Here we show that the developmental loss of responsiveness to LN-1 can be reversed by treatments that increase the activation state of integrins. Both extracellular application of Mn2+ (at micromolar concentrations)
and viral-mediated neuronal expression of a constitutively active form
of the ras-related GTPase R-ras (R-ras38V) potently
promoted late-embryonic retinal neurite outgrowth on LN-1 substrata. In
both cases, outgrowth was mediated by integrin  6 1 and not
31, even though these neurons express 31 and use it for
outgrowth on other laminin isoforms, as well as on LN-1 that has been
proteolytically or conformationally activated (Ivins et al., 1998).
Mn2+ and to a much lesser extent
R-ras38Valso reversed the developmental loss of
retinal neuron responsiveness to type IV collagen, by promoting the
function of integrin 11. Interestingly, the responses of other
late-embryonic CNS neurons to LN-1 were also enhanced by treatments
that activate integrin function, but those of peripheral nervous
system neurons (dorsal root ganglion neurons) were either not
enhanced (embryonic neurons) or only modestly improved (adult neurons).
These results suggest that a developmental decline occurs in the
activation state of neuronal integrins, particularly among CNS neurons.
Such a decline may underlie some of the intrinsic loss of regenerative
ability sustained by CNS neurons during development and may be a valid target for therapeutic intervention.
Key words:
R-ras; integrin activation; HSV; axon outgrowth; retina; regeneration
Copyright © 2000 Society for Neuroscience 0270-6474/00/20176551-10$05.00/0
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