Distinct Functional Domains of Neurofibromatosis Type 1 Regulate Immediate versus Long-Term Memory Formation

Abstract

Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors of the peripheral nervous system. In addition, Ͼ40% 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.

Identification of Genes That Promote or Inhibit Olfactory Memory Formation in Drosophila

“…Importantly, many of the genes already known to function in olfactory memory formation were identified in the RNAi screen, providing internal validation of the effectiveness of the screen ( Davis (2013) were recaptured in the RNAi screen, including the classical mutants dunce and rutabaga (Dudai et al 1976;Tempel et al 1983;Livingstone et al 1984;Folkers et al 1993;Connolly et al 1996;Moreau-Fauvarque et al 2002;Ho et al 2007;Knapek et al 2010;Madalan et al 2011). It was not expected that all known genes would be reidentified, since only a fraction of the genome was screened, some RNAi transgenes may not be functional, and the degree of knockdown by RNAi for some involved genes may be too slight to produce a phenotype.…”

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

“…However, the malignant phenotypes of neurofibromin-deficient MPNST cells cannot be totally rescued by the GAP domain reconstitution alone (38,39). Furthermore, RAStargeted therapeutic approaches, such as S-trans, trans-farnesylthiosalicylic acid, have provided limited efficacy in clinical studies of NF1 (8,40).…”

Proteomic and transcriptomic analysis of visual long-term memory in Drosophila melanogaster

“…In rats, an injection of MAPK/ ERK blocked LTM (Kelly et al, 2003), and knocking-out ERK1 in the mouse enhanced synaptic plasticity and memory (Mazzucchelli et al, 2002). In Drosophila, NF1 (Neurofibromin 1) was reported to play a role in LTM through the Ras/ MAPK pathway (Ho et al, 2007). These results suggest that P38c may be involved in LTM through the MAPK/ERK pathway.…”

“…To evaluate the reliability of up-regulation and downregulation of genes in comparison between 12-h STP and 12-h CTP groups, we chose five genes for quantitative PCR (qPCR): the genes strn-mlck and p38c are involved in MAPK/ ERK pathway, and the genes mthl2 and tld were reported to be involved in axon guidance and synaptic transmission (Aberle et al, 2002;Mazzucchelli et al, 2002;Kelly et al, 2003;Keshishian and Kim, 2004;Sharma and Carew., 2004;Ho et al, 2007), and an unknown gene CG1673. For qPCR experiments, 150 flies were trained by STP, and another 150 were trained by CTP.…”

“…In Drosophila, many genes were found to be involved in olfactory memory: cAMP associated rutabaga and dunce related to STM, amnesiac related to MTM, and radish related to ARM (Margulies et al, 2005). Several genes were also found to specifically influence LTM, such as nmda (Xia et al, 2005), crammer (Comas et al, 2004), nf1 (Ho et al, 2007), notch (Ge et al, 2004;Presente et al, 2004), AKAP Yu (Lu et al, 2007), Klingon (Matsuno et al, 2009), and ben (Zhao et al, 2009). Moreover, microarray analysis was used to detect gene expression changes at 0, 6, and 24 h between spaced training and massed training groups.…”