Originally identified as repulsive axon guidance cues, ephrins and their Eph receptors have since been implicated in many aspects of neural development, including tissue morphogenesis, cell migration, synapse formation and the development of dendritic spines. Shaping of spines requires rearrangement of the underlying actin cytoskeleton, and although cell biologists have identified many of the molecules involved in regulating this process, the link between cell surface receptors and the cytoskeletal machinery is not well understood. On page 1117 of this issue, Yamaguchi and colleagues identify the molecular mechanism linking Eph receptors to dendritic spine morphogenesis.

The crucial output of the cascade initiated by EphB receptor ligands is the activation of a Rho family GTPase, CDC-42, which controls the initiation and branching of actin filaments. The authors found that intersectin, a guanine nucleotide exchange factor (GEF) that activates CDC-42, associates with the EphB2 receptor and that this association activates the GEF activity of intersectin. Another activator of CDC-42, N-WASP (neural Wiskott-Aldrich syndrome protein), which links CDC-42 to actin filament initiation, also associates with this complex. The combined association of intersectin and N-WASP with the EphB receptor synergistically activates CDC-42.

CDC-42 is known to induce a complex branching pattern of actin filaments, consistent with the formation of the bulbous structure of dendritic spines (the punctate protrusions on dendrites in the hippocampal neuron shown at top). Expression of a dominant-negative CDC-42 would be predicted to result in a loss of branched actin filaments, and does indeed lead to the loss of dendritic spines in hippocampal cultures (bottom). In the presence of this inhibitor, spines are replaced by long, thin filopodia, consisting of a linear core of filamentous actin, consistent with the loss of CDC-42's actin branching activity.