Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.

Brannan, Camilynn I.; Perkins, Archibald S.; Vogel, Kristine S.; Ratner, Nancy; Nordlund, Michael L.; Reid, Susan W.; Buchberg, Arthur M.; Jenkins, Nancy A.; Parada, Luis F.; Copeland, Neal G.

doi:10.1101/gad.8.9.1019

Cited by 599 publications

(416 citation statements)

References 36 publications

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“…Nf1 þ /À mice 22 were mated to obtain primary MEF cultures of the three Nf1 genotypes. These cultures were utilized to establish SV40-immortalized MEFs (hereafter termed SV40 MEFs).…”

Section: Resultsmentioning

confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio-and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1 À/À , Nf1 þ /À , and Nf1 þ / þ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

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“…Nf1 þ /À mice 22 were mated to obtain primary MEF cultures of the three Nf1 genotypes. These cultures were utilized to establish SV40-immortalized MEFs (hereafter termed SV40 MEFs).…”

Section: Resultsmentioning

confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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“…Homozygous disruption of Nf1 in mice leads to embryonic lethality (*E12.5) whereas mice heterozygous for a targeted Nf1 mutation develop pheochromocytomas and leukemias, but not the typical tumors (neuro®bromas, astrocytomas) seen in individuals with NF1 (Brannan et al, 1994;Jacks et al, 1994). To determine whether a haploinsu cient e ect is observed in mice with reduced neuro®bromin expression, the number of glial ®brillary acidic protein (GFAP)-immunoreactive astrocytes from Nf1+/7 mouse brains were counted in several well-de®ned areas of the brain (corpus callosum, dentate gyrus, cerebellum and hippocampus CA1 region).…”

Section: Resultsmentioning

confidence: 99%

“…Nf1+/7 mice were generously provided by Dr Neal Copeland (National Cancer Institute) (Brannan et al, 1994). Gap+/7 mice have been previously described (Henkemeyer et al, 1995).…”

Section: Primary Astrocyte Culturesmentioning

confidence: 99%

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

et al. 1999

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Individuals a ected with neuro®bromatosis 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+/7) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neuro®bromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is su cient for abnormal astrocyte proliferation. Here, we report that Nf1+/7 mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/7 astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cellinduced Nf1+/7 increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-rasdependent e ect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These ®ndings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be su cient for the development of astrocytic growth abnormalities in patients with NF1.

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“…The early embryonic lethality of Nf1 À/À embryos precluded skeletal analyses [Brannan et al, 1994;Jacks et al, 1994;Lakkis and Epstein, 1998] and the first NF1 mouse bone study used Nf1 þ/À mice. Nf1 þ/À osteoprogenitors and osteoblasts had defects in proliferation and differentiation in vitro and constitutive activation of Ras and Erk signaling, as observed in Nf1 þ/À Schwann cells [Yu et al, 2005].…”

Section: Mouse Models and Pathophysiology Of Nf1mentioning

confidence: 99%

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

Elefteriou

Kolanczyk

Schindeler

et al. 2009

American J of Med Genetics Pt A

138

114

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The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials. © 2009 Wiley‐Liss, Inc.

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Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.

Cited by 599 publications

References 36 publications

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

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

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

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