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Human Molecular Genetics Advance Access published online on March 2, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl023
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 8, 2005
Revised February 7, 2006
Accepted February 7, 2006

Article

Effect of Neurofibromatosis Type I mutations on a novel pathway for Adenylyl Cyclase activation requiring Neurofibromin and Ras

Frances Hannan 1, Ivan Ho 2, Jiayuan Tong 3, Yinghua Zhu 4, Peter Nurnberg 5, and Yi Zhong 4 *

1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; New York Medical College, Valhalla, New York 10595, USA
2 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Graduate Program in Genetics, State University of New York at Stonybrook, New York 11794, USA
3 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Graduate Program in Neurobiology and Behavior, State University of New York at Stonybrook, New York 11794, USA
4 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
5 Institute for Medical Genetics, Charite, Humboldt University, 10098 Berlin, Germany.

* To whom correspondence should be addressed.
Yi Zhong, E-mail: zhongyi{at}cshl.edu


  Abstract

Neurofibromatosis Type I (NFI) is a common genetic disorder that causes nervous system tumours, and learning and memory defects in humans, and animal models. We identify a novel growth factor stimulated Adenylyl Cyclase (AC) pathway in the Drosophila brain, which is disrupted by mutations in the epidermal growth factor receptor (EGFR), neurofibromin (NF1) and Ras, but not G{alpha}s. This is the first demonstration in a metazoan that a receptor tyrosine kinase (RTK) pathway, acting independently of the heterotrimeric G-protein subunit G{alpha}s, can activate AC. We also show that G{alpha}s is the major G{alpha} isoform in fly brains, and define a second AC pathway stimulated by serotonin and histamine requiring NF1 and G{alpha}s, as well as a third, classical G{alpha}s-dependent AC pathway, which is stimulated by Phe-Met-Arg-Phe-amide (FMRFamide) and dopamine. Using mutations and deletions of the human NF1 protein (hNF1) expressed in Nf1 mutant flies, we show that Ras activation by hNF1 is essential for growth factor stimulation of AC activity. Further, we demonstrate that sequences in the C-terminal region of hNF1 are sufficient for NF1/ G{alpha}s-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies.


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