We therefore asked whether actomyosin activity regulated the size, shape, or location of the PSD in the spine. To study PSD morphology, we stained for the PDZ-containing synaptic scaffold protein PSD-95, which is a canonical PSD marker that appears early during PSD formation. Whereas control spines exhibit a compact, round, or slightly elliptical PSD, MIIB knockdown spines displayed an NVP-BEZ235 elongated PSD with larger perimeters. Furthermore, in control cells, PSD-95 localizes mainly to the spine tip; however, in MIIBdeficient neurons, the elongated PSD localizes away from the spine tip and base, toward the center of the filopodia-like spine. Similar results were observed using another PSD marker, shank, suggesting that MIIB controls the morphology of the PSD globally, rather than through specific effects on some of its constituents. Non-muscle myosin II plays a major role in the organization of actin filaments and dictates the diverse morphologies and directional movement of various cell types. These include the apical constriction of epithelial cells, nuclear positioning, orientation of the microtubule-organizing center, Golgi and the contractile ring of dividing cells, and polarization of migrating fibroblasts. Of the MII isoforms, MIIB is the predominant one found in hippocampal neurons, and its activity and effective affinity for actomyosin filaments is regulated by RLC. Previous studies have implicated MIIB as a target of a signaling pathway that is mutated in non-syndromic mental retardation and in spine development and memory formation. We now address the mechanisms by which MIIB acts on spines and show that differential MIIB activity determines where spines form, creates diverse post-synaptic spine morphologies, and mediates the morphology, size, and positioning of the PSD. It also mediates the changes in spine morphology in response to stimuli. Thus, MIIB emerges as a major downstream regulator of the component processes underlying post-synaptic plasticity, and implicitly, learning and memory. Spine maturation consists of three stages: emergence of protrusions along the dendritic shaft, spine elongation, and maturation into a mushroom-shape. Our results demonstrate that differential MIIB activity mediates and coordinates these diverse stages of spine development. Highly branched and dynamic spines emerge along the dendritic shaft and proceed to develop into the long dendritic protrusions that characterize immature spines, which persist in the absence of full, i.e., di-phosphorylated RLC, MIIB activation. This 53123-88-9 suggests that MIIB normally functions to restrict membrane protrusion and branching. It also suggests that the elongation of filopodia-like protrusions occurs in the absence of strong MIIB contractile activity. Several observations support this hypothesis. Myosin IIB inhibition or knockdown produces numerous long filopodia that do not mature. In addition, the contractile-deficient myosin IIB mutant, R709C, cross-links but does not contract actin and results in persistently long spines. Therefore, we blocked both caspase dependent cell death and JNK signaling in fly retina misexpressing Aß42. Blocking both caspase and JNK pathways simultaneously produced the protection against Aß42, suggesting that Aß42 induces cell death by several mechanisms. Our results suggest that blocking multiple pathways may result in significant protection against Aß42 neurotoxicity, an important consideration for potential AD therapies. JNK signaling pathway has been known to be involved in different processes of ageing and development, including tissue homeostasis, cell proliferation, cell survival and innate immune response. Interestingly, evidence collected in several models of AD supports the involvement of JNK signaling in AD. Consistent with our observations, Aß42 induces JNK activation in primary cultures of rat cortical neurons.