Defective Neuronal Development in the Mushroom Bodies ofDrosophila Fragile X Mental Retardation 1Mutants

Abstract

Fragile X mental retardation 1 (Fmr1) is a highly conserved gene with major roles in CNS structure and function. Its product, the RNA-binding protein FMRP, is believed to regulate translation of specific transcripts at postsynaptic sites in an activity-dependent manner. Hence, Fmr1 is central to the molecular mechanisms of synaptic plasticity required for normal neuronal maturation and cognitive ability. Mutations in its Drosophila ortholog, dfmr1, produce phenotypes of brain interneurons and axon terminals at the neuromuscular junction, as well as behavioral defects of circadian rhythms and courtship. We hypothesized that dfmr1 mutations would disrupt morphology of the mushroom bodies (MBs), highly plastic brain regions essential for many forms of learning and memory. We found developmental defects of MB lobe morphogenesis, of which the most common is a failure of ␤ lobes to stop at the brain midline. A similar recessive ␤-lobe midline-crossing phenotype has been previously reported in the memory mutant linotte. The dfmr1 MB defects are highly sensitive to genetic background, which is reminiscent of mammalian fragile-X phenotypes. Mutations of dfmr1 also interact with one or more third-chromosome loci to promote ␣/␤-lobe maturation. These data further support the use of the Drosophila model system for study of hereditary cognitive disorders of humans.

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].…”

“…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]. Carlos Michel and Robert Kraft in my lab found a specific developmental defect during the metamorphic transition [Michel et al, 2004], when hundreds of mushroom body ␣/␤ neurons are born and differentiate . Wild-type ␣/␤ axons bifurcate at right angles and project into vertical (␣) and medial (␤) lobes.…”

“…Wild-type ␣/␤ axons bifurcate at right angles and project into vertical (␣) and medial (␤) lobes. In dfmr1 mutants, axons project into the lobes at the appropriate developmental stage but, as they approach the midline, they fail to detect or to obey a "stop " signal [Michel et al, 2004]. Rather, they continue growing into the contralateral hemisphere, resulting in the appearance of ␤-lobe midline fusion, observable by confocal microscopy with appropriate fluorescent markers (Fig.…”

“…However, there is an important caveat when interpreting phenotypes in such mosaic animals, exemplified by the report that single-neuron dfmr1 mutant clones in the ␤ lobes do not show midline crossing [Pan et al, 2004]. This discrepancy provides an important clue, suggesting that the whole-brain mutant phenotype [Michel et al, 2004] is notcell-autonomous, but rather results from cell-cell interaction. The cell-autonomy issue has broader implications, for instance, for understanding the phenotypic variation of many X-linked MR disorders in heterozygous human females, whose brains are mosaic due to X-chromosome inactivation [e.g., Braunschweig et al, 2004].…”

“…In the dfmr1 mutant (B), the ␤-lobe axons have grown across the midline and fused with the contralateral fibers (arrow). [adapted from Michel et al, 2004].…”