Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation.
Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors of the peripheral nervous system. In addition, >40% of afflicted children have learning difficulties. The NF1 protein contains a highly conserved GTPase-activating protein domain that inhibits Ras activity, and the C-terminal region regulates cAMP levels via G-protein-dependent activation of adenylyl cyclase. Behavioral analysis indicates that learning is disrupted in both Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1 mutants. In the present report, our experiments showed that in addition to learning, long-term memory was also abolished in Nf1 mutants. However, altered NF1-regulated Ras activity is responsible for this defect rather than altered cAMP levels. Furthermore, by expressing clinically relevant human NF1 mutations and deletions in Drosophila Nf1-null mutants, we demonstrated that the GAP-related domain of NF1 was necessary and sufficient for long-term memory, whereas the C-terminal domain of NF1 was essential for immediate memory. Thus, we show that two separate functional domains of the same protein can participate independently in the formation of two distinct memory components.
Ho
Ivan Shun
IS
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Hannan
Frances
F
Guo
Hui-Fu
HF
Hakker
Inessa
I
Zhong
Yi
Y
D000818:Animals; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008568:Memory / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D025542:Neurofibromin 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012153:Retention, Psychology / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D029721:Drosophila Proteins; C105590:NF1 protein, Drosophila; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D020703:ras GTPase-Activating Proteins