Coupling of dynamic microtubules to F-actin by Fmn2 regulates chemotaxis of neuronal growth cones

Dynamic co-regulation of the actin and microtubule subsystems enables the highly precise and adaptive remodeling of the cytoskeleton necessary for critical cellular processes, like axonal pathfinding. The modes and mediators of this interpolymer crosstalk, however, are inadequately understood. We identify Fmn2, a non-diaphanous related formin associated with cognitive disabilities, as a novel regulator of cooperative actin-microtubule remodeling in growth cones. We show that Fmn2 stabilizes microtubules in the growth cones of cultured spinal neurons and also in vivo. Superresolution imaging revealed that Fmn2 facilitates guidance of exploratory microtubules along actin bundles into the chemosensory filopodia. Using live imaging, biochemistry and single-molecule assays we show that a C-terminal domain in Fmn2 is necessary for the dynamic association between microtubules and actin filaments. In the absence of the cross-bridging function of Fmn2, filopodial capture of microtubules is compromised resulting in de-stabilized filopodial protrusions and deficits in growth cone chemotaxis. Our results uncover a critical function for Fmn2 in actin-microtubule crosstalk in neurons and demonstrate that modulating microtubule dynamics via associations with F-actin is central to directional motility.