Formin-2 regulates stabilization of filopodial tip adhesions in growth cones and affects neuronal outgrowth and pathfinding in vivo

Abstract

Growth cone filopodia are actin-based mechanosensory structures essential for chemoreception and generation of contractile forces necessary for directional motility. However, little is known about the influence of filopodial actin structures on substrate adhesion and filopodial contractility. Formin-2 (Fmn2) localizes along filopodial actin bundles and its depletion does not affect filopodia initiation or elongation. However, Fmn2 activity is required for filopodial tip adhesion maturation and the ability of filopodia to generate traction forces. Dysregulation of filopodia in Fmn2 depleted neurons leads to compromised growth cone motility. Additionally, in fibroblasts, Fmn2 regulates ventral stress fiber assembly and affects the stability of focal adhesions. In the developing spinal cord, Fmn2 activity is required cell autonomously for the outgrowth and pathfinding of spinal commissural neurons. Our results reveal an unanticipated function for Fmn2 in neural development. Fmn2 regulates structurally diverse bundled actin structures, parallel filopodial bundles in growth cones and anti-parallel stress fibers in fibroblasts, in turn modulating the stability of substrate adhesions. We propose Fmn2 as a mediator of actin bundle integrity enabling efficient force transmission to the adhesion sites.