Actin regulatory mechanisms during spine development and plasticity. (A) Spine development starts with the initiation of the dendritic filopodium and its elongation. Eps8 inhibits filopodia initiation by its capping activity. We propose that Ena/VASP proteins could induce filopodia elongation from Arp2/3 complex–generated branched filaments by anti-capping the actin barbed ends. (B) mDia2 promotes actin filament polymerization in the filopodium tip. We propose that Ena/VASP and myosin X take part in filopodia elongation. At this stage, the elongation of dendritic filopodia protrusions is mechanistically more similar to the promotion of lamellipodia protrusions. The factors driving actin filament polymerization in the base of filopodia remain to be identified. (C) Extensive actin branching occurs at the filopodium tip and the spine head begins to form. The mechanism of actin assembly is now increased and the large Arp2/3-nucleated branched actin filament network leads to enlargement of the spine head. The function of ADF/cofilins, in addition to replenishing the cytoplasmic actin monomer pool in neurons, is to control the proper length of actin filaments and thus to prevent formation of abnormal protrusions from spine heads. (D) Mature spines are still dynamic but maintain their overall morphology. Dynamics occur as small Arp2/3 complex–induced protrusions on the surface of the spine head (morphing). Myosin II–dependent contractility and cross-linking of actin filaments further modulate the shape of the spine head. We propose that during LTP, the activities of Arp2/3, profilin, actin cross-linking proteins, myosin II, and actin filament capping proteins are increased whereas activity of cofilin is reduced. The actin-ring structure is oversimplified to highlight the possible dynamic changes in the spine head morphology.