The cytoskeletal regulator Farp1 organizes synapse and dendrite development

Synapse and dendrite development are tightly coordinated processes that are guided largely by extrinsic factors such as synaptic input and extracellular molecular interactions. However, the signaling mechanisms that link extracellular cues to the dynamic cytoskeletal changes that characterize neuronal differentiation are insufficiently understood. In the present study, we used quantitative proteomics to screen for intracellular signaling partners of the synaptogenic adhesion molecule SynCAM 1 and identified Farp1 as significantly reduced in the synapses of SynCAM 1 knock-out mice. My biochemical analysis determined that Farp1 is a synaptic protein that is most highly expressed in the brain during development. At synapses, Farp1 forms a complex with SynCAM 1 through its FERM domain. In cultured hippocampal neurons, Farp1 increases filopodial dynamics and lifetimes during early development and increases excitatory synapse numbers later on. Interestingly, SynCAM 1 requires Farp1 to promote synapse formation, while Farp1 is sufficient to increase synapse numbers even in SynCAM 1 knock-out neurons. Live imaging of fluorescent probes indicates that Farp1 activates the Rho GTPase Rad to promote F-actin assembly in synaptic spines. These studies present the Farpl/Racl signaling axis as the first known mechanism linking SynCAM 1 to actin dynamics during synaptogenesis. In addition to early roles in synapse formation, Farp1 also promotes dendritic complexity later at a time point when arbors are maturing. Importantly, Semaphorin3A signaling through PlexinAl requires Farpl to drive dendritic arborization, while Farpi is necessary and sufficient to increase branching. Even after activity blockade, Farpl increases both dendritic complexity and spine numbers. Conversely, Sema3A-dependent branching through Farpl requires neuronal activity, indicating that Farpl may be controlled by multiple divergent mechanisms. Chronic blockade of activity leads to a depletion of total PlexinAl levels as well as a translocation of Farpl from dendritic shafts into spines, and these effects may underlie the dependence of Sema3A-driven branching on activity. As at synapses, Farpl promotes F-actin assembly within dendritic shafts, an effect that is augmented by Sema3A treatment and may represent a downstream mechanism whereby Sema3A can control cytoskeletal dynamics. Overall, these studies describe important roles for the cytoskeletal regulator Farpl in mediating synapse and dendrite development downstream of synaptic adhesion and extracellular molecular signaling.