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Vol. 19, Issue 11, 4804-4813, November 2008

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Actin Filament Assembly by Myristoylated, Alanine-rich C Kinase Substrate–Phosphatidylinositol-4,5-diphosphate Signaling Is Critical for Dendrite Branching

Haimin Li^*, Gang Chen^*,, Bing Zhou^*, and Shumin Duan^*

*Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China; and Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, People's Republic of China

Submitted March 19, 2008; Revised August 26, 2008; Accepted September 5, 2008
Monitoring Editor: Paul Forscher

Dendrites undergo extensive growth and branching at early stages, but relatively little is known about the molecular mechanisms underlying these processes. Here, we show that increasing the level of myristoylated, alanine-rich C kinase substrate (MARCKS), a prominent substrate of protein kinase C and a phosphatidylinositol-4,5-diphosphate [PI(4,5)P2] sequestration protein highly expressed in the brain, enhanced branching and growth of dendrites both in vitro and in vivo. Conversely, knockdown of endogenous MARCKS by RNA interference reduced dendritic arborization. Results from expression of different mutants indicated that membrane binding is essential for MARCKS-induced dendritic morphogenesis. Furthermore, MARCKS increased the number and length of filamentous actin-based filopodia along neurites, as well as the motility of filopodia, in a PI(4,5)P2-dependent manner. Time-lapse imaging showed that MARCKS increased frequency of filopodia initiation but did not affect filopodia longevity, suggesting that MARCKS may increase dendritic branching through its action on filopodia initiation. These findings demonstrate a critical role for MARCKS–PI(4,5)P2 signaling in regulating dendrite development.

Lab homepage: http://www.ion.ac.cn/laboratories/duanshumin/index.htm.

Address correspondence to: Shumin Duan (shumin{at}ion.ac.cn)

Abbreviations used: 3'-UTR, 3'-untranslated region; ABP, actin-binding protein; Arp2/3, actin-related protein 2/3; BK, bradykinin; DIV, days in vitro; ED, effector domain; F-actin, filamentous actin; LTA, latrunculin A; MARCKS, myristoylated, alanine-rich C kinase substrate; PAO, phenylarsine oxide; PH, pleckstrin homology; PI(4,5)P2, phosphatidylinositol-4,5-diphosphate; PKC, protein kinase C; PLC, phospholipase C; PN, postnatal day; RNAi, RNA interference; shRNA, short hairpin RNA.