Astrocyte-Specific Inactivation of the Neurofibromatosis 1 Gene (NF1) Is Insufficient for Astrocytoma Formation

Abstract

Individuals with the neurofibromatosis 1 (NF1) inherited tumor syndrome develop low-grade gliomas (astrocytomas) at an increased frequency, suggesting that the NF1 gene is a critical growth regulator for astrocytes. In an effort to determine the contribution of the NF1 gene product, neurofibromin, to astrocyte growth regulation and NF1-associated astrocytoma formation, we generated astrocyte-specific Nf1 conditional knockout mice (Nf1^GFAPCKO) by using Cre/LoxP technology. Transgenic mice were developed in which Cre recombinase was specifically expressed in astrocytes by embryonic day 14.5. Successive intercrossing with mice bearing a conditional Nf1 allele (Nf1flox) resulted in GFAP-Cre Nf1flox/flox (Nf1^GFAPCKO) animals. No astrocytoma formation or neurological impairment was observed in Nf1^GFAPCKO mice after 20 months, but increased numbers of proliferating astrocytes were observed in several brain regions. To determine the consequence of Nf1 inactivation at different developmental times, the growth properties of embryonic day 12.5 and postnatal day 2 Nf1 null astrocytes were analyzed. Nf1 null astrocytes exhibited increased proliferation but lacked tumorigenic properties in vitro and did not form tumors when injected into immunocompromised mouse brains in vivo. Collectively, our results suggest that loss of neurofibromin is not sufficient for astrocytoma formation in mice and that other genetic or environmental factors might influence NF1-associated glioma tumorigenesis.

This work was supported by funding from the National Institutes of Health (NS36996 to D.H.G.). M.L.B. is supported by a National Research Service Award fellowship from the National Eye Institute (1F32 EY14039-01).

We thank S. K. Song for the MRI studies as well as YanLi Wu, Lisa Fink, Sean Brophy, and Rebecca Baldwin for technical assistance during the execution of these experiments. We thank Abhijit Guha, David Holtzman, Alexander Parsadanian, Selva Baltan-Tekkok, Mercedes Salvador, and Rosario Hernandez for comments and discussions. We also thank Anthony Apicelli for helpful discussions.