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Vol. 19, Issue 12, 5181-5192, December 2008

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The Scaffold Protein POSH Regulates Axon Outgrowth

Jennifer Taylor^*,, Kwan-Ho Chung^,,, Claudia Figueroa^*,||, Jonathan Zurawski^*,||, Heather M. Dickson^*, E. J. Brace^*, Adam W. Avery^*, David L. Turner^*,,, and Anne B. Vojtek^*

*Department of Biological Chemistry, Program in Neuroscience, and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109

Submitted February 29, 2008; Revised August 28, 2008; Accepted September 23, 2008
Monitoring Editor: Paul Forscher

How scaffold proteins integrate signaling pathways with cytoskeletal components to drive axon outgrowth is not well understood. We report here that the multidomain scaffold protein Plenty of SH3s (POSH) regulates axon outgrowth. Reduction of POSH function by RNA interference (RNAi) enhances axon outgrowth in differentiating mouse primary cortical neurons and in neurons derived from mouse P19 cells, suggesting POSH negatively regulates axon outgrowth. Complementation analysis reveals a requirement for the third Src homology (SH) 3 domain of POSH, and we find that the actomyosin regulatory protein Shroom3 interacts with this domain of POSH. Inhibition of Shroom3 expression by RNAi leads to increased process lengths, as observed for POSH RNAi, suggesting that POSH and Shroom function together to inhibit process outgrowth. Complementation analysis and interference of protein function by dominant-negative approaches suggest that Shroom3 recruits Rho kinase to inhibit process outgrowth. Furthermore, inhibition of myosin II function reverses the POSH or Shroom3 RNAi phenotype, indicating a role for myosin II regulation as a target of the POSH–Shroom complex. Collectively, these results suggest that the molecular scaffold protein POSH assembles an inhibitory complex that links to the actin–myosin network to regulate neuronal process outgrowth.

These authors contributed equally to this work.

^|| These authors contributed equally to this work.

Address correspondence to: Anne B. Vojtek (avojtek{at}umich.edu)