Mical is a direct link between semaphorins–plexins and the F-actin cytoskeleton. Semaphorins directly bind to the extracellular portion of plexins on the cell surface, and plexins directly interact via their cytoplasmic domain with the C-terminus of Mical present within cells. Mical then mediates actin reorganization by direct association of its NADPH/redox domain with F-actin.

Semaphorins belong to a large family of secreted and membrane-bound proteins that are involved in the regulation of actin dynamics. Recent evidence indicates that the Mical family of enzymes associate with semaphorin receptors, known as plexins, to mediate axon guidance and cell morphological changes. In Nature, Jon Terman and colleagues now show that Mical directly controls semaphorin–plexin-mediated F-actin reorganization.

Bristles of Drosophila melanogaster are actin-rich cellular extensions that are formed during pupal development. Using this model system, the authors set out to investigate the role of Mical in actin dynamics. First, they found that bristles lacking Mical (Mical^−/−) or overexpressing functional Mical have abnormal morphologies; expression of functional Mical in Mical^−/− bristles rescued these defects. They then show that bristles expressing Mical with mutations in either its redox domain (Mical^Δredox) or calponin homology (CH) domain (Mical^ΔCH) had Mical^−/−–like abnormal morphologies, whereas bristles expressing both the Mical redox and CH domains (Mical^redoxCH) alone displayed morphologies similar to those in Mical-overexpressing flies. This indicates that both the redox and CH domains of Mical are necessary and together they are sufficient for directing bristle morphology.

But what are the molecular mechanisms by which Mical mediates changes in bristle morphology? The authors demonstrate that Mical colocalizes with F-actin at the tips of growing bristles. Furthermore, direct visualization of actin in developing bristles revealed that in Mical^−/− bristles, F-actin bundles are much thicker than normal, whereas either Mical overexpression or expression of Mical^redoxCH results in much thinner F-actin bundles. Importantly, increased Mical activity (in Mical-overexpressing or Mical^redoxCH-expressing bristles) generated F-actin reorganization, resulting in a complex meshwork of short actin filaments, rather than the normal, parallel-bundled F-actin. The authors further found that purified Mical^redox or Mical^redoxCH protein binds to F-actin and that activating the redox activity of Mical with its NADPH coenzyme reduces actin polymerization and increases F-actin disassembly, showing that Mical directly alters actin dynamics in an NADPH/redox-dependent manner. Taken together, these data indicate that Mical is a critical F-actin-regulating protein that controls actin dynamics and rearranges F-actin bundles into a complex meshwork, similarly to cytoskeletal reorganization during lamellipodia formation in motile cells.

So, what are the signalling mechanisms involved in Mical-mediated F-actin disassembly? Micals are known to associate with the cytoplasmic portion of plexins. Consistently, fluorescence imaging of developing bristle processes revealed that Mical, semaphorins and plexin-A colocalize to the growing bristle tips in close association with F-actin. Modifying the expression levels of plexin A or its transmembrane semaphorin ligands resulted in morphological and F-actin defects similar to those in which Mical expression was altered. Moreover, both loss-of-function and dominant-negative Mical mutants inhibited the plexin-A-dependent alterations in bristles.

In this study, Terman and colleagues present a model in which Mical provides the physical link between semaphorin-bound plexin and the F-actin cytoskeleton through its redox and CH domains, and that semaphorin–plexin–Mical signalling mediates actin cytoskeletal reorganization.

Author: Iley Ozerlat - Copyright © 2010 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission