Regulation of dendritic spine morphogenesis by PSD-95

Eunjoon Kim

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea

e-mail: kime@kaist.ac.kr

The small GTPases Rac1 and Cdc42 are key regulators of the morphogenesis of actin-rich dendritic spines in neurons, but detailed mechanisms are not well known. We discovered that the PSD-95-associated key postsynaptic density (PSD) protein Shank interacts with and promotes synaptic targeting of beta-PIX, a GEF for the Rac1 and Cdc42, and the beta-PIX-associated signaling molecule PAK, an effector kinase of Rac1/Cdc42. We also found that another key PSD protein PSD-95 associates with and promotes synaptic localization of IRSp53, which links activated Rac1/Cdc42 to downstream effectors for actin regulation. Overexpression of IRSp53 increases the density of dendritic spines. Conversely, RNAi knockdown of IRSp53 reduces the density, length, and width of spines. The density and size of spines are decreased by a dominant-negative IRSp53 mutant and a dominant-negative proline-rich region of WAVE2, a downstream effector of IRSp53. These results suggest that Shank and PSD-95 interactions are important determinants of synaptic bPIX and IRSp53 localizations, respectively, and that Shank and PSD-95 play important roles in the organization of the Rac1 signaling pathway at synapses for the regulation of spine morphogenesis.