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Molecular and Cellular Biology, February 2002, p. 1150-1157, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1150-1157.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Neurofibromatosis Type 2 Gene Product, merlin, Reverses the F-Actin Cytoskeletal Defects in Primary Human Schwannoma Cells

Anne-Marie Bashour,1 J.-J. Meng,1 Wallace Ip,1 Mia MacCollin,2 and Nancy Ratner1*

Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267,1 Neurology Unit, Massachusetts General Hospital East, Charlestown, Massachusetts 021292

Received 13 June 2001/ Returned for modification 20 August 2001/ Accepted 2 November 2001

Schwannoma tumors, which occur sporadically and in patients with neurofibromatosis, account for 8% of intracranial tumors and can only be treated by surgical removal. Most schwannomas have biallelic mutations in the NF2 tumor suppressor gene. We previously showed that schwannoma-derived Schwann cells exhibit membrane ruffling and aberrant cell spreading when plated onto laminin, indicative of fundamental F-actin cytoskeletal defects. Here we expand these observations to a large group of sporadic and NF2-related tumors and extend them to schwannomatosis-derived tumors. Mutation at NF2 correlated with F-actin abnormalities, but the extent of morphological change did not correlate with the type of NF2 mutation. We used a recently described molecular strategy, TAT-mediated protein transfer, to acutely introduce the NF2 protein, merlin, into primary human schwannoma cells in an attempt to reverse the cytoskeletal phenotype. Abnormal ruffling and cell spreading by cells with identified NF2 mutations were rapidly reversed by introduction of TAT-merlin. The effect is specific to TAT-merlin isoform 1, the growth-suppressive isoform of merlin. TAT-merlin isoform 2, a TAT-merlin mutant (L64P), and merlin lacking TAT were ineffective in reversing the cytoskeletal phenotype. Results show that merlin isoform 1 is sufficient to restore normal actin organization in NF2-deficient human tumor cells, demonstrating a key role for merlin in the NF2 phenotype. These results lay the foundation for epigenetic complementation studies in NF2 mouse models and possibly for experiments to evaluate the utility of merlin transduction into patients as protein therapy.

* Corresponding author. Mailing address: Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267. Phone: (513) 558-6079. Fax: (513) 558-4454. E-mail: nancy.ratner{at}uc.edu.

Molecular and Cellular Biology, February 2002, p. 1150-1157, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1150-1157.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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