Mical links semaphorins to F-actin disassembly

Abstract

Semaphorins and plexins relay guidance information to neurons during development and regulate actin dynamics through an unknown mechanism. In recent studies, a family of oxidoreductase enzymes called Mical were found to associate with plexins and mediate axon guidance. Hung et al. demonstrate that in Drosophila, Mical is an F-actin-binding protein that links plexins and semaphorins to the actin cytoskeleton. Changing the levels of Mical in vivo result in reorganization of the actin cytoskeleton, indicating that Mical is required for maintaining the normal size and organization of F-actin bundles. Thus, plexins on the cell surface modulate the actin cytoskeleton via the Mical oxidoreductase. Semaphorins and their receptors, plexins, relay guidance information to neurons during development and regulate actin dynamics through an unknown mechanism. Recently, proteins of the Mical family of enzymes have been found to associate with plexins; here, Mical is reported to directly link semaphorins and their plexin receptors to the precise control of actin filament dynamics. How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer1. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes2, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways3, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes4,5,6,7. Mical enzymes perform reduction–oxidation (redox) enzymatic reactions4,5,8,9,10 and also contain domains found in proteins that regulate cell morphology4,11. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin–plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganization—a hallmark of cell morphological changes including axon navigation—can be precisely achieved spatiotemporally in response to semaphorins.