Abstract
Neurofibromatosis type 1 (NF1) is a dominant genetic disorder characterized by multiple benign and malignant nervous system tumors, and by learning defects in 45% of children with NF1 mutations. Studies of neurofibromin, the protein encoded by NF1, have focused on its functions in tumorigenesis and regulation of Ras activity; however, Drosophila NF1 regulates both Ras and cyclic AMP (cAMP) pathways. Expression of a human NF1 transgene rescued cAMP-related phenotypes in NF1 mutant flies (small body size and G protein–stimulated adenylyl cyclase (AC) activity defects), and neuropeptide– and G protein–stimulated AC activity were lower in Nf1−/− as compared to Nf1+/− mouse brains, demonstrating that neurofibromin regulates AC activity in both mammals and flies.
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Acknowledgements
We thank I. Hakker, J. An and J. Coblentz for technical help. This work was supported by grants to Y.Z. from the US National Institutes of Health (NS34779), US Army (DAMD17-99-1-9500), Neurofibromatosis Foundation, Massachusetts Bay area and Neurofibromatosis Foundation, Illinois.
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Supplementary Figure 1
Developmental AC activity profiles. AC activity was assayed using membrane fractions extracted from mouse frontal lobes at each developmental stage, including embryonic day 12.5 (E12.5), postnatal day 1 (P1) and adult (3 month). All data were obtained from wild-type mice. Extracts from each individual were divided into three; number of assays for each data point, n = 3. Data are expressed as mean ± s.e.m.. Stimulated AC activities were significantly higher in all situations (p < 0.01; two-tailed Student's t-test). (GIF 26 kb)
Supplementary Figure 2
Similar expression levels of the stimulatory G protein a-subunit in Nf1 knockout versus wild-type mice. A representative example of immunoblots of Gsa with antisera from Calbiochem (1:1,000) after SDS-PAGE electrophoresis is shown. No obvious disruption was seen. Frontal brain tissues from Nf1+/+, Nf1+/- and Nf1-/- littermates were homogenized for western blot analysis. Molecular-weight markers are indicated. Three independent analyses were performed. (JPG 5 kb)
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Tong, J., Hannan, F., Zhu, Y. et al. Neurofibromin regulates G protein–stimulated adenylyl cyclase activity. Nat Neurosci 5, 95–96 (2002). https://doi.org/10.1038/nn792
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DOI: https://doi.org/10.1038/nn792
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