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Mical links semaphorins to F-actin disassembly


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.

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Figure 1: Mical regulates actin-rich cellular process morphology.
Figure 2: Semaphorin, plexin and Mical control F-actin organization and bundling.
Figure 3: Semaphorin–plexin-mediated actin rearrangements require Mical, which binds and directly regulates actin dynamics.
Figure 4: Mical directly disassembles F-actin and regulates growth cone morphology.


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We thank C. Cowan, M. Rosen and T. Südhof for comments on drafts of our manuscript and M. Bailey, C. Gilpin, H. He, T. Januszewski, H. Krämer, W. Lin, T. Wedgeworth, X. Zhang and the University of Texas Southwestern Electron Microscopy Core Facility for discussions and assistance. We also thank the Bloomington, Harvard and Japanese stock centres for flies and H. Aberle, L. Cooley, C. Goodman, A. Kolodkin, B. Lee, L. Luo, J. Merriam and X. Zhang for flies and/or reagents. This work was supported by the US National Institute of Mental Health (MH085923) and a Basil O’Connor Starter Scholar Research Award to J.R.T. J.R.T. is a Klingenstein Fellow and the Rita C. and William P. Clements, Jr, Scholar in Medical Research.

Author Contributions All authors contributed critical reagents, discussed the results and commented on the manuscript; R.-J.H., U.Y., J.Y., H.W., T.Y. and J.R.T. performed experiments, collected and analysed data, and prepared the manuscript; and J.R.T. oversaw all aspects of the project and wrote the paper.

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Correspondence to Jonathan R. Terman.

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Hung, RJ., Yazdani, U., Yoon, J. et al. Mical links semaphorins to F-actin disassembly. Nature 463, 823–827 (2010).

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