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Human Molecular Genetics, 2001, Vol. 10, No. 26 3009-3016
© 2001 Oxford University Press

Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes

David H. Gutmann+, Yan Li Wu, Nicolé M. Hedrick, Yuan Zhu1, Abhijit Guha2 and Luis F. Parada1

Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA, 1Center for Developmental Biology and The Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX, USA and 2Department of Neurosurgery, University of Toronto, Toronto, Canada

Individuals with the neurofibromatosis 1 (NF1) tumor predisposition syndrome develop low-grade pilocytic astrocytomas at an increased frequency. Previously, we demonstrated that astrocytes from mice heterozygous for a targeted mutation in the Nf1 gene (Nf1+/– astrocytes) exhibit a cell autonomous growth advantage associated with increased RAS pathway activation. In this report, we extend our initial characterization of the effect of reduced Nf1 gene expression on astrocyte function by demonstrating that Nf1+/– astrocytes exhibit decreased cell attachment, actin cytoskeletal abnormalities during the initial phases of cell spreading, and increased cell motility. Whereas these cytoskeletal abnormalities were also observed in Nf1–/– astrocytes, astrocytes expressing a constitutively active RAS molecule showed increased cell motility and abnormal actin cytoskeleton organization during cell spreading, but exhibited normal cell attachment. Based on ongoing gene expression profiling experiments on human astrocytoma tumors, we demonstrate increased expression of two proteins implicated in cell attachment, spreading and motility (GAP43 and T-cadherin) in Nf1+/– and Nf1–/– astrocytes. These results support the emerging notion that tumor suppressor gene heterozygosity results in abnormalities in cell function that may contribute to the pathogenesis of non-tumor phenotypes in NF1.

+ To whom correspondence should be addressed. Tel: +1 314 362 7149; Fax: +1 314 362 2388; Email: gutmannd@neuro.wustl.edu


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