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A neurofibromatosis-1-regulated pathway is required for learning in Drosophila

Nature volume 403, pages 895–898 (2000)Cite this article

Abstract

The tumour-suppressor gene Neurofibromatosis 1 (Nf1) encodes a Ras-specific GTPase activating protein (Ras-GAP)1,2,3,4,5. In addition to being involved in tumour formation6,7, NF1 has been reported to cause learning defects in humans8,9,10 and Nf1 knockout mice11. However, it remains to be determined whether the observed learning defect is secondary to abnormal development. The Drosophila NF1 protein is highly conserved, showing 60% identity of its 2,803 amino acids with human NF1 (ref. 12). Previous studies have suggested that Drosophila NF1 acts not only as a Ras-GAP but also as a possible regulator of the cAMP pathway that involves the rutabaga (rut)-encoded adenylyl cyclase13. Because rut was isolated as a learning and short-term memory mutant14,15, we have pursued the hypothesis that NF1 may affect learning through its control of the Rut-adenylyl cyclase/cAMP pathway. Here we show that NF1 affects learning and short-term memory independently of its developmental effects. We show that G-protein-activated adenylyl cyclase activity consists of NF1-independent and NF1-dependent components, and that the mechanism of the NF1-dependent activation of the Rut-adenylyl cyclase pathway is essential for mediating Drosophila learning and memory.

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Figure 1: Rescue of the NF1 learning defect by inducible expression of the normal NF1 transgene.
Figure 2: Effects of the cAMP pathway on NF1-dependent learning and memory.
Figure 3: Biochemical assay of the effects of NF1 on AC activity.

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Acknowledgements

We thank T. Tully for help with behavioural assays, R. Davis for extensive comments on the manuscript, and A. Bernards for providing the fly stocks. This work was supported by a Pew Scholarship, grants from NIH, grants from Texas Neurofibromatosis foundation, NF Inc. Mass Bay Aere and Illinois NF Inc., Perkin fund, and donations from M. L. Rankowitz and S. H. Heffron to Y.Z., and by a National Neurofibromatosis Foundation Young Investigator Award to F.H.

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  1. Hui-Fu Guo and Jiayuan Tong: These authors contributed equally to this work

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, P.O. Box 100, Cold Spring Harbor, 11724, New York, USA

    Hui-Fu Guo, Jiayuan Tong, Frances Hannan, Lin Luo & Yi Zhong

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Guo, HF., Tong, J., Hannan, F. et al. A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 403, 895–898 (2000). https://doi.org/10.1038/35002593

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