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GENES & DEVELOPMENT 19:2307-2319, 2005
©2005 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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RESEARCH PAPER

The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones

Baris Tursun1,5, Anne Schlüter1,5, Marvin A. Peters1, Birte Viehweger1, Heather P. Ostendorff1, Juliana Soosairajah2, Alexander Drung1,3, Michael Bossenz1, Steven A. Johnsen1, Michaela Schweizer1, Ora Bernard2 and Ingolf Bach1,3,4,6

1 Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, 20251 Hamburg, Germany; 2 The Walter and Eliza Hall Institute for Medical Research, Victoria 3050, Australia; 3 Program in Gene Function & Expression, 4 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324, USA

LIM kinase 1 (LIMK1) controls important cellular functions such as morphogenesis, cell motility, tumor cell metastasis, development of neuronal projections, and growth cone actin dynamics. We have investigated the role of the RING finger protein Rnf6 during neuronal development and detected high Rnf6 protein levels in developing axonal projections of motor and DRG neurons during mouse embryogenesis as well as cultured hippocampal neurons. RNAi-mediated knock-down experiments in primary hippocampal neurons identified Rnf6 as a regulator of axon outgrowth. Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. Rnf6 is functionally linked to LIMK1 during the development of axons, as the changes in axon outgrowth induced by up- or down-regulation of Rnf6 levels can be restored by modulation of LIMK1 expression. Thus, these results assign a specific role for Rnf6 in the control of cellular LIMK1 concentrations and indicate a new function for the ubiquitin/proteasome system in regulating local growth cone actin dynamics.

[Keywords: LIM kinase; actin cytoskeleton; axon development; primary hippocampal neurons; protein stability; ubiquitin; proteasome]

Received June 6, 2005; revised version accepted August 10, 2005.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1340605.

5 These authors contributed equally to this work.

6 Corresponding author.

E-MAIL Ingolf.Bach{at}umassmed.edu; FAX (508) 856-4650.


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