title: Fragile x mental retardation 1 and filamin a interact genetically in Drosophila long-term memory.
abstract: The last decade has witnessed the identification of single-gene defects associated with an impressive number of mental retardation syndromes. Fragile X syndrome, the most common cause of mental retardation for instance, results from disruption of the FMR1 gene. Similarly, Periventricular Nodular Heterotopia, which includes cerebral malformation, epilepsy and cognitive disabilities, derives from disruption of the Filamin A gene. While it remains unclear whether defects in common molecular pathways may underlie the cognitive dysfunction of these various syndromes, defects in cytoskeletal structure nonetheless appear to be common to several mental retardation syndromes. FMR1 is known to interact with Rac, profilin, PAK and Ras, which are associated with dendritic spine defects. In Drosophila, disruptions of the dFmr1 gene impair long-term memory (LTM), and the Filamin A homolog (cheerio) was identified in a behavioral screen for LTM mutants. Thus, we investigated the possible interaction between cheerio and dFmr1 during LTM formation in Drosophila. We show that LTM specifically is defective in dFmr1/cheerio double heterozygotes, while it is normal in single heterozygotes for either dFmr1 or cheerio. In dFmr1 mutants, Filamin (Cheerio) levels are lower than normal after spaced training. These observations support the notion that decreased actin cross-linking may underlie the persistence of long and thin dendritic spines in Fragile X patients and animal models. More generally, our results represent the first demonstration of a genetic interaction between mental retardation genes in an in vivo model system of memory formation.
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor New York, NY, USA.
authors.forename: François V
authors.initials: FV
authors.lastname: Bolduc
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bell
authors.forename: Cory
authors.initials: C
authors.lastname: Rosenfelt
authors.forename: Hilary
authors.initials: H
authors.lastname: Cox
authors.forename: Tim
authors.initials: T
authors.lastname: Tully