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Outgrowth of Neurites from NIE-115 Neuroblastoma Cells Is Prevented on Repulsive Substrates through the Action of PAK

Katharine J. M. Marler,¹ Robert Kozma,^1,2, Sohail Ahmed,^1,2, Jing-Ming Dong,^1,2 Christine Hall,¹ and Louis Lim^1,2*

Department of Molecular Neuroscience, Institute of Neurology, University College London, 1 Wakefield St., London WC1N 1PJ, United Kingdom,¹ GSK-IMCB Group, Institute of Molecular & Cell Biology, Proteos, 61 Biopolis Dr., Singapore 138673, Singapore²

Received 25 August 2004/ Returned for modification 21 October 2004/ Accepted 17 March 2005

In the central nervous system (CNS), damaged axons are inhibited from regeneration by glial scars, where secreted chondroitin sulfate proteoglycan (CSPG) and tenascin repulse outgrowth of neurites, the forerunners of axons and dendrites. During differentiation, these molecules are thought to form boundaries for guiding neurons to their correct targets. In neuroblastoma NIE-115 cells, outgrowth of neurites on laminin could be induced by serum starvation or inhibition of RhoA by Clostridium botulinum C3 toxin. The outgrowing neurites avoided crossing onto the repulsive substrate CSPG or tenascin. This avoidance response was partially overcome on expression of membrane-targeted and kinase-inactive forms of PAK. In these cells, the endogenous PAK isoforms colocalized with actin in distinctive sites, PAK in the cell center as small clusters and along the neurite shaft and ßPAK and PAK in areas with membrane ruffles and filopodia, respectively. When isoform-specific N-terminal PAK sequences were introduced to interfere with PAK function, substantially more neurites crossed onto CSPG when cells contained a PAK-derived peptide but not the corresponding PAK- or ßPAK-derived peptide. Thus, while neurite outgrowth can be promoted by RhoA inhibition, overcoming the accompanying repulsive guidance response will require modulation of PAK activity. These results have therapeutic implications for CNS repair processes.

Present address: Genome Institute of Singapore, 60 Biopolis St., Singapore 138672.

Present address: Institute of Molecular & Cell Biology, 61 Biopolis Dr., Singapore 138673.

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