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Vol. 15, Issue 7, 3433-3449, July 2004

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LIMK1 Regulates Golgi Dynamics, Traffic of Golgi-derived Vesicles, and Process Extension in Primary Cultured Neurons

Silvana Rosso ^* , Flavia Bollati ^* , Mariano Bisbal ^*, Diego Peretti ^*, Tomoyuki Sumi , Toshikazu Nakamura , Santiago Quiroga , Adriana Ferreira ^||, and Alfredo Cáceres ^* ¶

^* Instituto Investigacion Medica Mercedes y Martin Ferreya-CONICET-Consejo Nacional de Investigaciones Científicas y Técnicas, 5000 Cordoba, Argentina; Division of Biochemistry, Osaka University Medical School, Osaka 565-0871, Japan; Centro Investigacion Quimica Biologica Cordoba-CONICET-Consejo Nacional de Investigaciones Científicas y Técnicas, 5000 Cordoba, Argentina; and ^|| Institute for Neuroscience and Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611

Submitted May 23, 2003; Revised March 30, 2004; Accepted April 9, 2004
Monitoring Editor: Anne Ridley

In this study, we examined the subcellular distribution and functions of LIMK1 in developing neurons. Confocal microscopy, subcellular fractionation, and expression of several epitope-tagged LIMK1 constructs revealed that LIMK1 is enriched in the Golgi apparatus and growth cones, with the LIM domain required for Golgi localization and the PDZ domain for its presence at neuritic tips. Overexpression of wild-type LIMK1 suppresses the formation of trans-Golgi derived tubules, and prevents cytochalasin D-induced Golgi fragmentation, whereas that of a kinase-defective mutant has the opposite effect. Transfection of wild-type LIMK1 accelerates axon formation and enhances the accumulation of Par3/Par6, insulin-like growth factor (IGF)1 receptors, and neural cell adhesion molecule (NCAM) at growth cones, while inhibiting the Golgi export of synaptophysin-containing vesicles. These effects were dependent on the Golgi localization of LIMK1, paralleled by an increase in cofilin phosphorylation and phalloidin staining in the region of the Golgi apparatus, and prevented by coexpression of constitutive active cofilin. The long-term overexpression of LIMK1 produces growth cone collapse and axon retraction, an effect that is dependent on its growth cone localization. Together, our results suggest an important role for LIMK1 in axon formation that is related with its ability to regulate Golgi dynamics, membrane traffic, and actin cytoskeletal organization.

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

These authors contributed equally to this study.

^¶ Corresponding author. E-mail address: acaceres{at}immf.uncor.edu.

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