title: 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(GFAP)CKO) 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(GFAP)CKO) animals. No astrocytoma formation or neurological impairment was observed in Nf1(GFAP)CKO 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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Michaela Livia
authors.initials: ML
authors.lastname: Bajenaru
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Nicolé M
authors.initials: NM
authors.lastname: Hedrick
authors.forename: Jessica
authors.initials: J
authors.lastname: Donahoe
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001254:Astrocytoma / Q000209:etiology* / Q000235:genetics; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D016514:Genes, Neurofibromatosis 1; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006801:Humans; D019426:Integrases / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014764:Viral Proteins / Q000235:genetics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases