This proposal utilizes Drosophila models for investigating mechanisms and functions of the tumor suppressor gene neurofibromatosis 1 (NF1). We are particularly interested in its role in regulation of G-protein-dependent activation of the cAMP pathway. NF1 protein contains a fragment homologous to catalytic domain of the Ras-specific GAPS and its mutations cause a common neurogenetic disorder that is identified by neurofibromas and other symptoms including specific learning defects. Our study of Drosophila NF1 mutants has revealed that in addition to as a Ras-GAP, NF1 is involved in regulation of G-protein dependent activation of adenylyl cyclase (AC) encoded by rutabaga gene. This NF1-regulated cAMP pathway is crucial for mediating a neuropeptide response at neuromuscular junction, body size development, and learning and memory. However, it is unclear how NF1 regulates AC activity, how the NF1-regulated AC pathway contributes to learning and memory, and whether such NF1-regulated mechanism also works in vertebrates. The proposal is intended to investigate these problems. It includes two specific aims. 1) Eighteen point mutations identified in human NF1 patients will be used to define which parts of NF1 is important for regulation of AC activity and whether Ras is involved in such regulation. Then mouse Nf1 knockout mutants will be used to assay whether NF1 can regulate AC activity in vertebrates. 2) Biochemical and electrophysiological analyses will be directed to determine neurotransmitters that activate NF1-regulated AC activity in the fly brain and neurotransmitters that activate the NF1-regulated AC pathway to modulate membrane currents in identified mushroom body neurons. These neurons have been suggested to be involved in the associative learning process that are disrupted by NF1 mutations. We expect that the proposed research will lead to new insights into NF1 function and provide new clues for understanding pathogenesis of NF1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034779-07
Application #
6539850
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Finkelstein, Robert
Project Start
1996-02-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
7
Fiscal Year
2002
Total Cost
$290,500
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Chiang, Hsueh-Cheng; Wang, Lei; Xie, Zuolei et al. (2010) PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila. Proc Natl Acad Sci U S A 107:7060-5
de Bivort, Benjamin Lovegren; Guo, Hui-Fu; Zhong, Yi (2009) Notch signaling is required for activity-dependent synaptic plasticity at the Drosophila neuromuscular junction. J Neurogenet 23:395-404
Chiang, Hsueh-Cheng; Iijima, Koichi; Hakker, Inessa et al. (2009) Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions. FASEB J 23:1969-77
Ho, Ivan Shun; Hannan, Frances; Guo, Hui-Fu et al. (2007) Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation. J Neurosci 27:6852-7
Hannan, Frances; Ho, Ivan; Tong, James Jiayuan et al. (2006) Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras. Hum Mol Genet 15:1087-98
Guo, Hui-Fu; Zhong, Yi (2006) Requirement of Akt to mediate long-term synaptic depression in Drosophila. J Neurosci 26:4004-14
Zhong, Yi; Wu, Chun-Fang (2004) Neuronal activity and adenylyl cyclase in environment-dependent plasticity of axonal outgrowth in Drosophila. J Neurosci 24:1439-45
Tong, Jiayuan; Hannan, Frances; Zhu, Yinghua et al. (2002) Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci 5:95-6
Wang, Y; Wright, N J; Guo, H et al. (2001) Genetic manipulation of the odor-evoked distributed neural activity in the Drosophila mushroom body. Neuron 29:267-76
Hannan, F; Zhong, Y (1999) Second messenger systems underlying plasticity at the neuromuscular junction. Int Rev Neurobiol 43:119-38

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