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 Zhu, Abhijit Guha, Luis F. Parada

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3009-3016
Number of pages8
JournalHuman Molecular Genetics
Volume10
Issue number26
StatePublished - Dec 15 2001

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Neurofibromatosis 1
Astrocytes
Neurofibromatosis 1 Genes
Neoplasms
Astrocytoma
Cell Movement
Gene Expression Profiling
Tumor Suppressor Genes
Actin Cytoskeleton
Actins
Phenotype
Gene Expression
Mutation
Growth

ASJC Scopus subject areas

  • Genetics

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Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes. / Gutmann, David H.; Wu, Yan Li; Hedrick, Nicolé M.; Zhu, Yuan; Guha, Abhijit; Parada, Luis F.

In: Human Molecular Genetics, Vol. 10, No. 26, 15.12.2001, p. 3009-3016.

Research output: Contribution to journalArticle

Gutmann, David H. ; Wu, Yan Li ; Hedrick, Nicolé M. ; Zhu, Yuan ; Guha, Abhijit ; Parada, Luis F. / Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 26. pp. 3009-3016.
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