Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth

The establishment of neural circuits depends on the ability of axonal growth cones to sense their surrounding environment en route to their target. To achieve this, a coordinated rearrangement of cytoskeleton in response to extracellular cues is essential. Although previous studies have identified different chemotropic and adhesion molecules that influence axonal development, the molecular mechanism by which these signals control the cytoskeleton remains poorly understood. Here, we show that in vivo conditional ablation of the focal adhesion kinase gene (Fak) from mouse hippocampal pyramidal cells impairs axon outgrowth and growth cone morphology during development, which leads to functional defects in neuronal connectivity. Time-lapse recordings and in vitro FRAP analysis indicate that filopodia motility is altered in growth cones lacking FAK, probably owing to deficient actin turnover. We reveal the intracellular pathway that underlies this process and describe how phosphorylation of the actin nucleation-promoting factor NWASP is required for FAK-dependent filopodia formation. Our study reveals a novel mechanism through which FAK controls filopodia formation and actin nucleation during axonal development. © 2012. Published by The Company of Biologists Ltd.
This work was supported by grants from the Marie Curie International Reintegration Program of the European Commission through Research Project Contract SYNAPSON [MIRG-CT-2004-013082 to B.R.]; the Spanish Government [BFU2004-00349, SAF2007-61904, SAF2010-21723, to B.R.; SAF2010-20604 to R.S.; BFU2010-17537 to M.M.; and CONSOLIDER CSD2007-00023 to B.R.]; and the following Foundations: Areces, Reina Sofía, Rioja Salud (to M.M.) and Alicia Koplowitz (to B.R.). B.R. is a European Molecular Biology Organization (EMBO) Young Investigator.