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

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 formation 6 , 7 , NF1 has been reported to cause learning defects in humans 8 , 9 , 10 and Nf1 knockout mice 11 . 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 13 . Because rut was isolated as a learning and short-term memory mutant 14 , 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.