XMAP215 promotes microtubule-F-actin interactions to regulate growth cone microtubules during axon guidance

Abstract

It has long been established that neuronal growth cone navigation depends on changes in microtubule (MT) and F-actin architecture downstream of guidance cues. However, the mechanisms by which MTs and F-actin are dually-coordinated remain a fundamentally unresolved question. Here, we report that the well-characterized MT polymerase, XMAP215, plays an important role in mediating MT-F-actin interaction within the growth cone. We demonstrate that XMAP215 regulates MT-F-actin alignment through its amino-terminal TOG 1-5 domains. Additionally, we show that XMAP215 directly binds to F-actin in vitro and co-localizes with F-actin in the growth cone periphery. We also find that XMAP215 is required for regulation of growth cone morphology and response to the guidance cue, EphrinA5. Our findings provide the first strong evidence that XMAP215 coordinates MT and F-actin interaction in vivo. We suggest a model in which XMAP215 regulates MT extension along F-actin bundles into the growth cone periphery and that these interactions may be important to control cytoskeletal dynamics downstream of guidance cues.