verbatim): Type I neurofibromatosis (NF1) is an autosomal dominant disorder that strikes 1 in 3000 individuals. It is characterized by anomalies of diverse cell types, many of which are derived from the neural crest. The severity of these phenotypes can vary greatly even among individuals from the same family who carry the same mutation. The NF1 gene product, neurofibromin, is a cytoplasmic protein that exhibits structural and functional homology to the family of GTPase activating proteins that function as regulators of Ras oncoproteins. The group has generated a mouse model of NF1 that permits inactivation of the Nf1 gene in specific cells and tissues. This model affords a unique system for testing the role of this tumor suppressor protein in the regulation of signals in a variety of cell types including the neural crest, Schwann cells, fibroblasts, neurons, astrocytes and oligodendrocytes. This application concerns the further development and analysis of conditional mutant Nf1 mouse strains to analyze the role of neurofibromin in normal and malignant cells.
The specific aims are: 1) To characterize the consequences of neurofibromin loss for growth properties in primary neuronal and Schwann cell culture assays. 2) The group has applied genetic approaches to cross a neuron-specific synapsin-cre into the conditional Nf1 mutant. The consequences of Nf1 loss will be analyzed in a variety of neuronal systems. 3) A P0-cre mouse has been crossed with the Nf1 mutants. This P0 strain expresses mutant Nf1 in the entire neural crest and the resultant mice are embryonic lethal. The group plans to perform a battery of cellular and molecular assays similar to those performed in analysis of the original null Nf1 mutation to determine the extent of neural crest involvement. Additional P0-cre mice will be obtained to further study Nf1 loss in more confined neural crest derived compartments. 4) The group has intercrossed the Nf1 mutation into a GFAP-cre transgenic mouse. These mice exhibit dramatic behavioral abnormalities and die prematurely. Mice lacking neurofibromin function in GFAP-expressing cells will be studied for the properties of astrocytes in vivo and the consequences of neurofibromin loss. The availability of reliable in vivo models to study the role of neurofibromin in neurotrophin function is of critical importance for further evaluation of this suppressor oncogene in human disease, in programmed cell death, and in neural development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034296-06
Application #
6363891
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (01))
Program Officer
Finkelstein, Robert
Project Start
1995-08-01
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
6
Fiscal Year
2001
Total Cost
$390,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Zhu, Y; Romero, M I; Ghosh, P et al. (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 15:859-76
Parada, L F (2000) Neurofibromatosis type 1. Biochim Biophys Acta 1471:M13-9
Klesse, L J; Meyers, K A; Marshall, C J et al. (1999) Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells. Oncogene 18:2055-68
Vogel, K S; Klesse, L J; Velasco-Miguel, S et al. (1999) Mouse tumor model for neurofibromatosis type 1. Science 286:2176-9
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Vogel, K S; Parada, L F (1998) Sympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibromin. Mol Cell Neurosci 11:19-28