Mutations in the neurofibromatosis 2 (NF2) gene are the predominant cause in the development of sporadic schwannomas and are also involved in the pathogenesis of meningiomas and ependymomas. The product of the NF2 gene, termed merlin or schwannomin, is thought to act as a tumor suppressor protein. Although its protein sequence shows homology to proteins that are known to link the cytoskeleton to the cell membrane, no direct evidence for this function has been obtained. We used antisense phosphorothioate oligodeoxynucleotides (pODNs) complementary to the human NF2 cDNA sequence and transfected them into Schwann-like STS26T cells permeabilized by streptolysin 0. Changes in cell morphology and attachment were observed at 12 to 24 h and continued up to 48 h post transfection. Cells were rounded and easily dislodged from the substratum at 12-24 h. These changes were reversible and cells became bipolar with thin protrusions and began to reattach to the substratum after 48 h. Normal morphology and adhesion were observed at 72 h post transfection. Morphological changes were due to suppression of schwannomin synthesis. Immunoprecipitations with antischwannomin antibodies showed schwannomin to be almost absent 3 h after treatment with antisense pODNs and to be significantly suppressed up to 12 h post transfection whereas beta-actin levels remained unchanged. The morphological changes were not the result of cell death, but resulted in increased cell proliferation. These data demonstrate that antisense oligonucleotides can be successfully employed to suppress schwannomin synthesis and indicate that schwannomin may belong to a class of tumor suppressor genes that provide a link between cell adhesion and tumorigenesis.