Disease relevance of Fmr1

• We have developed a Drosophila fragile X syndrome model using loss-of-function mutants and overexpression of the FMR1 homolog (dfxr). dfxr nulls display enlarged synaptic terminals, whereas neuronal overexpression results in fewer and larger synaptic boutons [1].
• The characterization of dfxr function in the testes paves the way to genetic screens for modifiers of dfxr-induced male sterility, as a means to efficiently dissect FMRP-mediated mechanisms [2].
• A screen for modifiers of decapentaplegic mutant phenotypes identifies lilliputian, the only member of the Fragile-X/Burkitt's Lymphoma family of transcription factors in Drosophila melanogaster [3].

Psychiatry related information on Fmr1

• Loss of Fragile X mental retardation protein (FMRP) function causes the highly prevalent Fragile X syndrome [1 and 2] [4].
• 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 [5].

High impact information on Fmr1

• Fragile X-related protein and VIG associate with the RNA interference machinery [6].
• Through the awesome power of Drosophila genetics, two recent studies reveal novel mechanisms by which the Fragile X Mental Retardation protein regulates selective mRNA translation, controlling key steps of germline development during oogenesis and neuronal development during synaptogenesis [7].
• Using two different Drosophila melanogaster models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis [8].
• Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP) [8].
• FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes [8].

Biological context of Fmr1

• We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae [9].
• The frequency of central pair microtubule loss becomes progressively greater as spermatogenesis progresses, suggesting that dFXR regulates microtubule stability [2].
• Male dfxr null mutants have the enlarged testes characteristic of the disease and are nearly sterile (>90% reduced male fecundity). dFXR protein is highly enriched in Drosophila testes, particularly in spermatogenic cells during the early stages of spermatogenesis [2].
• Interestingly, distinct neuronal cell types show different phenotypes, suggesting that dfxr differentially regulates diverse targets in the brain [10].
• Fragile X mental retardation is a prominent genetic disorder caused by the lack of the FMR1 gene product, a known RNA binding protein [5].

Anatomical context of Fmr1

• We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1 loss-of-function mutations increased the number of higher-order dendritic branches [9].
• Taken together, these data show that dFMRP is a potent negative regulator of neuronal architecture and synaptic differentiation in both peripheral and central nervous systems [11].
• Here, we investigate dFXR function in the testes [2].
• Ultrastructurally, dfxr mutants lose specifically the central pair microtubules in the sperm tail axoneme [2].
• We previously established a FraX model in Drosophila, showing that the fly FMRP homologue, dFXR, acts as a negative translational regulator of microtubule-associated Futsch to control stability of the microtubule cytoskeleton during nervous system development [2].

Associations of Fmr1 with chemical compounds

• They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients [12].
• The substitutions of conserved isoleucine residues within the KH domains with asparagine are thought to impair binding of RNA substrates and perhaps the ability of FMRP to assemble into mRNP complexes [13].

Regulatory relationships of Fmr1

• Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk) [14].

Other interactions of Fmr1

• These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect [9].
• CYFIP mutations affect axons and synapses, much like mutations in dFMR1 (the Drosophila FMR1 ortholog) and in Rho GTPase dRac1 [15].
• Moreover, Rac1-induced actin remodeling is altered in fibroblasts lacking FMRP or carrying a point-mutation in the KH1 or in the KH2 RNA-binding domain [16].
• Furthermore, we show that dFMRP associates with endogenous tral mRNA and is required for normal TRAL protein expression and localization, revealing it as a previously undescribed target of dFMRP control [17].
• In addition, dosage compensation is controlled by Sex-lethal-mediated translational regulation while dFMR1 (the Drosophila homologue of the fragile X mental retardation protein) controls translation of various mRNAs which function in the nervous system [18].

Analytical, diagnostic and therapeutic context of Fmr1

• Several RNA-binding domains have been identified in FMRP, but the contribution of these individual domains to FMRP function in an animal model is not well understood [13].

References