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First published online 28 March 2006
doi: 10.1242/jcs.02884

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Profilin-I-ligand interactions influence various aspects of neuronal differentiation

Anja Lambrechts^1,*, Veronique Jonckheere¹, Christa Peleman^1,, Debby Polet¹, Winnok De Vos², Joël Vandekerckhove¹ and Christophe Ampe¹

¹ Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, and Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB09), Albert Baertsoenkaai 3, 9000 Ghent, Belgium
² Department of Molecular Biotechnology, Faculty of Bio-engineer sciences, Ghent University, 9000 Ghent, Belgium

^* Author for correspondence (e-mail: anja.lambrechts{at}Ugent.be)

Accepted 4 January 2006

Differentiating neurons extend membrane protrusions that develop into growing neurites. The driving force for neurite outgrowth is the dynamic actin cytoskeleton, which is regulated by actin-binding proteins. In this study, we describe for the first time, the role of profilin I and its ligand interactions in neuritogenesis of PC12 cells. High-level overexpression of wild-type profilin I had an inhibitory effect on neurite outgrowth. Low levels of profilin I did not disturb this process, but these cells developed many more filopodia along the neurite shafts. Low-level overexpression of mutant forms of profilin I changed one or more aspects of PC12 differentiation. Expression of a profilin I mutant that is defective in actin binding (profilin I^R74E) decreased neurite length and strongly inhibited filopodia formation. Cells expressing mutants defective in binding proline-rich ligands (profilin I^W3A and profilin I^R136D) differentiated faster, developed more and longer neurites and more branches. The profilin I^R136D mutant, which is also defective in phosphatidylinositol 4,5-bisphosphate binding, enhanced neurite outgrowth even in the absence of NGF. Parental PC12 cells treated with the ROCK inhibitor Y27632, differentiate faster and display longer neurites and more branches. Similar effects were seen in cells expressing profilin I^WT, profilin I^W3A and profilin I^R74E. By contrast, the profilin I^R136D-expressing cells were insensitive to the ROCK inhibitor, suggesting that regulation of profilin I by phosphatidylinositol 4,5-bisphosphate metabolism is crucial for proper neurite outgrowth. Taken together, our data show the importance of the interaction of profilin I with actin, proline-rich proteins and phosphatidylinositol 4,5-bisphosphate in neuronal differentiation of PC12 cells.

Key words: Profilin mutants, Actin, PC12, Neuritogenesis, PtdIns(4,5)P₂

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