Recent work has made it clear that Sema3A signaling involves several intracellular pathways mediating a variety of cellular responses (for review, see Pasterkamp and Kolodkin, 2003). Semaphorins are an important class of extracellular guidance cues, and Sema3A is the prototypical axonal repellant. Thus, complex Plex/CRMP/MICAL interactions transduce Semaphorin signaling into axon guidance.Īccurate axonal guidance during development is essential for neuronal function. A constitutively active CRMP mutant inhibits MICAL activity more potently than does wild-type CRMP, suggesting that CRMP or a CRMP-associated factor is a MICAL substrate. In addition to acting as an upstream MICAL activator, CRMP functions downstream of MICAL, inhibiting the catalytic domain. CRMP and Plexin associate with nonenzymatic and enzymatic domains of MICAL and together release MICAL enzymatic autoinhibition. MICAL enzymatic activity is inhibited by the C-terminal domain of MICAL. Here, we show that CRMP and MICAL physically associate and that Sema signaling promotes this association. The relationship between CRMP and MICAL signaling has not been defined nor is the mechanism by which Plexin activates MICAL clear. Two families of cytoplasmic proteins, collapsin response mediator proteins (CRMPs) and molecules interacting with CasL (MICALs), have been implicated in Plexin function. Semaphorin activation of Plexin (Plex) receptors provides axonal guidance during neuronal development.