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The Journal of Neuroscience, May 3, 2006, 26(18):4961-4969; doi:10.1523/JNEUROSCI.0704-06.2006

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Development/Plasticity/Repair
RanBPM Contributes to Semaphorin3A Signaling through Plexin-A Receptors

Hideaki Togashi, ^* Eric F. Schmidt, ^* and Stephen M. Strittmatter

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510

Correspondence should be addressed to Stephen M. Strittmatter, Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06510. Email: stephen.strittmatter{at}yale.edu

Secreted Semaphorin3A (Sema3A) proteins are known to act as diffusible and repellant axonal guidance cues during nervous system development. A receptor complex consisting of a Neuropilin and a Plexin-A mediates their effects. Plexin-A signal transduction has remained poorly defined despite the documented involvement of collapsin response mediator protein and molecule interacting with CasL proteins (MICALs) as mediators of Plexin-A activation. Here, we defined a domain of Plexin-A1 required for Sema3A signaling in a reconstituted environment and then searched for proteins interacting with this domain. RanBPM is shown to physically interact with Plexin-A1, and the RanBPM/Plexin complex is regulated by MICAL expression. Overexpression of RanBPM cooperates with PlexinA1 to reduce non-neuronal cell spreading and strongly inhibit axonal outgrowth in vitro and in vivo. A truncated RanBPM protein blocks Sema3A responsiveness in non-neuronal and neuronal cells. Suppression of RanBPM expression reduces Sema3A responsiveness. Thus, RanBPM is a mediator of Sema3A signaling through Plexin-A. RanBPM has the potential to link Plexin-A receptors to retrograde transport and microtubule function in axonal guidance.

Key words: Plexin; Neuropilin; Semaphorin; RanBPM; axonal guidance; growth cone collapse; CRMP

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Received Aug. 6, 2005; revised April 1, 2006; accepted April 3, 2006.

Correspondence should be addressed to Stephen M. Strittmatter, Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06510. Email: stephen.strittmatter{at}yale.edu

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