Drosophila Lacking dfmr1 Activity Show Defects in Circadian Output and Fail to Maintain Courtship Interest

Abstract

Fragile X mental retardation is a prominent genetic disorder caused by the lack of the FMR1 gene product, a known RNA binding protein. Specific physiologic pathways regulated by FMR1 function have yet to be identified. Adult dfmr1 (also called dfxr) mutant flies display arrhythmic circadian activity and have erratic patterns of locomotor activity, whereas overexpression of dFMR1 leads to a lengthened period. dfmr1 mutant males also display reduced courtship activity which appears to result from their inability to maintain courtship interest. Molecular analysis fails to reveal any defects in the expression of clock components; however, the CREB output is affected. Morphological analysis of neurons required for normal circadian behavior reveals subtle abnormalities, suggesting that defects in axonal pathfinding or synapse formation may cause the observed behavioral defects.

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…The cellular neural phenotypes of dfmr1 mutant flies are qualitatively similar to the mammalian ones, with a common-but not universal-theme of dendritic and axonal overgrowth in CNS and PNS, as well as pathfinding errors [Zhang et al, 2001;Dockendorff et al, 2002;Morales et al, 2002;Lee et al, 2003;Michel et al, 2004;Pan et al, 2004]. The only neurons for which both axonal and dendritic morphologies have been examined in dfmr1 mutants are those of the mushroom bodies, a brain region well known for its role in many forms of associative learning and memory [Zars, 2000;Roman and Davis, 2001;Heisenberg, 2003].…”

“…This phenotype is reminiscent of the aberrant sleep patterns and elevated melatonin levels found in FXS males [Gould et al, 2000]. Finally, "courtship interest" is reduced in dfmr1 mutant males [Dockendorff et al, 2002], but the residual level can still be reduced further by courtship conditioning [McBride et al, 2005]. As with the memory defect, courtship interest was restored by mGluR blockade during development or adulthood, whereas the activity rhythm phenotype was not [McBride et al, 2005].…”

“…Because the eclosion of the locomotor rhythm is intact, (the emergence of the adult fly from its protective cocoon-like structure at the end of metamorphosis) the locomotor rhythm defect reflects abnormal output of the circadian clock rather than a broken central oscillator [Dockendorff et al, 2002;Inoue et al, 2002;Morales et al, 2002]. This phenotype is reminiscent of the aberrant sleep patterns and elevated melatonin levels found in FXS males [Gould et al, 2000].…”

“…Behavioral phenotypes are more difficult to compare. Is the reduced courtship interest of dfmr1 mutant males [Dockendorff et al, 2002] a reflection of reduced libido or is it a counterpart of social anxiety and avoidance seen in FXS males [Cornish et al, 2004]? For now, I would argue that the phenotypic details may matter less than the molecular pathways underlying them, for, if mechanisms are similar, then drug-based treatments should be similar as well.…”

New insights into fragile X syndrome: from molecules to neurobehaviors

“…Physiological consequences of FMRP deficiency in the brain To improve our understanding of the physiological functions of FMRP in the brain, both the Fmr1-knockout mouse and the recently developed dfmr1-mutant flies have been studied [3,9,15,31,40,41]. Previous research has shown that the Fmr1-knockout mouse has subtle defects in behavior and spatial learning compared with wild-type mice [3].…”