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Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

Oncogene volume 18, pages 4450–4459 (1999)Cite this article

Abstract

Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/−) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf1+/− mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/− astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were co-cultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/− increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.

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Acknowledgements

We appreciate the advice of Drs Marga Behrens, M Livia Bajenaru, Mark Goldberg, and David Holtzman. This work was supported by funding from the NIH (NS33494) and generous support from Schnuck Markets, Inc.

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Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, Missouri, USA

    David H Gutmann, Allison Loehr, Yujing Zhang, Joanna Kim & Amanda Cashen

  2. University of Texas-Southwestern, Dallas, TX 75235, Texas, USA

    Mark Henkemeyer

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Gutmann, D., Loehr, A., Zhang, Y. et al. Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene 18, 4450–4459 (1999). https://doi.org/10.1038/sj.onc.1202829

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