The fragile X gene FMR1 participates in control of the mammalian circadian clock
Fragile X syndrome, the most common heritable cause of mental retardation, is caused by loss-of-function mutations in the fragile X mental retardation (FMR1) gene resulting in the absence of the gene product (FMRP). FMRP belongs to a family of proteins that includes the Fragile X related proteins 1 and 2 (FXRP1 & FXRP2). FXRPs share high similarity in their functional domains with FMRP and have been shown to interact with FMRP. It is likely that FXRPs play redundant roles with FMRP. Drosophila mutants lacking the orthologous DFXR show altered circadian activity. We therefore examined circadian rhythm in WT, Fmr1 knockout, Fxr2 knockout and Fmr1/Fxr2 double knockout mice using a circadian locomotor activity assay. We found that double knockout animals lack any circadian rhythm in their activity, even when in light-dark conditions. This is a highly unusual phenotype, which has not been found in the fly DFXR mutant, or in any other mouse mutations studied to date. We have investigated expression of the known clock components and find several that are abnormally cycling in the double knockout mice, in both the suprachiasmatic nucleus (SCN) and in the periphery (liver). Using an in vitro transfection assay, we can demonstrate that Fxr2 and Fmr1 can exert control over expression of both the Per1 and Per2 promoters, and are in the process of determining process by which these proteins control expression. These data suggest a role for the Fmr1 gene family in control of the mammalian central oscillator, a finding that may have significance to understanding learning and memory deficiencies in human patients.