Regulation of neurite outgrowth by integrin activation.
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 Mn(2+) (at micromolar concentrations) and viral-mediated neuronal expression of a constitutively active form of the ras-related GTPase R-ras (R-ras(38V)) potently promoted late-embryonic retinal neurite outgrowth on LN-1 substrata. In both cases, outgrowth was mediated by integrin alpha6beta1 and not alpha3beta1, even though these neurons express alpha3beta1 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). Mn(2+)-and to a much lesser extent R-ras(38V)-also reversed the developmental loss of retinal neuron responsiveness to type IV collagen, by promoting the function of integrin alpha1beta1. 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.
Ivins
J K
JK
Department of Developmental and Cell Biology and the Developmental Biology Center, University of California at Irvine, Irvine, California 92697, USA. jkivins@uci.edu
Yurchenco
P D
PD
Lander
A D
AD
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003094:Collagen; D004622:Embryo, Mammalian; D005109:Extracellular Matrix / Q000502:physiology; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology; D016023:Integrins / Q000502:physiology*; D007797:Laminin / Q000502:physiology*; D008345:Manganese / Q000494:pharmacology; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000166:cytology; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D016023:Integrins; D007797:Laminin; D011993:Recombinant Fusion Proteins; C121346:laminin 1; D020703:ras GTPase-Activating Proteins; D008345:Manganese; D003094:Collagen