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

Nature. 2000 Feb 24;403(6772):895-8. doi: 10.1038/35002593.


The tumour-suppressor gene Neurofibromatosis 1 (Nf1) encodes a Ras-specific GTPase activating protein (Ras-GAP). In addition to being involved in tumour formation, NF1 has been reported to cause learning defects in humans and Nf1 knockout mice. 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 cyclase. Because rut was isolated as a learning and short-term memory mutant, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Calcium / metabolism
  • Conditioning, Classical
  • Cyclic AMP / metabolism
  • Drosophila / genetics
  • Drosophila / physiology*
  • Drosophila Proteins*
  • Electric Stimulation
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • Heat-Shock Response
  • Insect Proteins / genetics
  • Insect Proteins / physiology*
  • Learning / physiology*
  • Memory, Short-Term / physiology
  • Mutation
  • Nerve Tissue Proteins*
  • Smell / physiology
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / physiology*


  • Drosophila Proteins
  • Insect Proteins
  • NF1 protein, Drosophila
  • Nerve Tissue Proteins
  • ras GTPase-Activating Proteins
  • Cyclic AMP
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Calcium