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Vol. 15, Issue 5, 2205-2217, May 2004

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Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs

Catherine Gauthier-Campbell ^*, David S. Bredt , Timothy H. Murphy ^*, and Alaa El-Din El-Husseini ^* 

^* Department of Psychiatry and the Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3; Department of Physiology, University of California at San Francisco, San Francisco, California 94143-0444

Submitted July 15, 2003; Revised February 1, 2004; Accepted February 2, 2004
Monitoring Editor: Lawrence Goldstein

Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes.

Abbreviations used: ARF6, ADP-ribosylation factor 6; GAP-43, growth-associated protein 43; EGFP, enhanced green fluorescent protein; PSD-95, postsynaptic density 95; DIV, days in vitro.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: alaa{at}interchange.ubc.ca.

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