Kathie L. Eagleson (a), Aurea F. Pimenta (a), Mary M. Burns (b), Liane D. Fairfull (c), Pamela K. Cornuet (d), Li Zhang (c) and Pat Levitt (a)
Molecular and Cellular Neuroscience, Volume 24, Issue 3 , November 2003, Pages 725-740
(a) John F. Kennedy Center for Research on Human Development and Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
(b) Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, USA
(c) Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
(d) Department of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Received 6 March 2003; revised 3 June 2003; accepted 26 June 2003; Available online 28 September 2003.
Abstract
The limbic system-associated membrane protein (LAMP) is a glycosylphosphatidylinositol-anchored glycoprotein with three immunoglobulin (Ig) domains that can either enhance or inhibit neurite outgrowth depending upon the neuronal population examined. In the present study, we investigate the domains responsible for these activities. Domain deletion revealed that the N-terminal IgI domain is necessary and sufficient for the neurite-promoting activity observed in hippocampal neurons. In contrast, inhibition of neurite outgrowth in SCG neurons, which is mediated by heterophilic interactions, requires full-length LAMP, although selective inhibition of the second Ig domain, but not the first or third domains, prevented the inhibitory effect. This indicates that the IgII domain of LAMP harbors the neurite-inhibiting activity, but only in the context of the full-length configuration. Covasphere-binding analyses demonstrate IgI/IgI interactions, but no interaction between IgII and any other domain, consistent with the biological activities that each domain mediates. The data suggest that LAMP may serve as a bifunctional guidance molecule, with distinct structural domains contributing to the promotion and inhibition of neurite outgrowth.
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