Regulation of neurite outgrowth by integrin activation

During late-embryonic development, retinal neurons lose the ability to atta ch and extend neurites on the extracellular matrix molecule laminin-1 (LN-1 ), despite the fact that they retain expression of integrin receptors for L N-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 r as-related GTPase R-ras (R-ras (38V)) potently promoted late-embryonic reti nal neurite outgrowth on LN-1 substrata. In both cases, outgrowth was media ted by integrin alpha 6 beta 1 and not alpha 3 beta 1, even though these ne urons express a3b1 and use it for outgrowth on other laminin isoforms, as w ell as on LN-1 that has been proteolytically or conformationally activated (Ivins et al., 1998). Mn2+ -and to a much lesser extent R-ras (38V) -also r eversed the developmental loss of retinal neuron responsiveness to type IV collagen, by promoting the function of integrin alpha 1 beta 1. Interesting ly, the responses of other late-embryonic CNS neurons to LN-1 were also enh anced by treatments that activate integrin function, but those of periphera l nervous system neurons (dorsal root ganglion neurons) were either not enh anced (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 CN S neurons during development and may be a valid target for therapeutic inte rvention.