Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.
"Although higher cognition is difficult to test in mice, recent research using a touchscreen operant conditioning paradigm (which facilitates a conflict between sensory-driven and task-dependent signals, thereby increasing cognitive load) demonstrates that Fmr1 KO mice display defects in learning under heavy cognitive demand (Dickson et al., 2013). The Drosophila FXS model similarly shows disruptions closely resembling human FXS patients, including hyperactivity , learning/memory deficits, and social interaction abnormalities (Bolduc et al., 2008, 2010a,b; Coffee et al., 2010, 2012; Tessier and Broadie, 2012). "
[Show abstract][Hide abstract] ABSTRACT: Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent (A-D) developmental processes are specifically impaired in autism spectrum disorders (ASDs). ASD genetic models in both mouse and Drosophila have pioneered our insights into normal A-D neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic fragile X syndrome (FXS), a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in A-D critical period processes. The fragile X mental retardation protein (FMRP) is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the A-D remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor A-D processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of A-D mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model.
"Only human FMR1 rescues the broad range of neurological phenotypes caused by dFMR1 KO, with human FXR1/2 having no activity, showing that FMR1 function has been evolutionarily conserved and that human FMR1 requirements can be effectively dissected in the Drosophila FXS disease model [84, 99]. Like human patients and the mouse model, dFMR1 KO flies exhibit synaptic overgrowth and synaptic immaturity in a range of neural circuits, including motor neurons [84, 86, 99], clock neurons [84, 87, 88, 99], and learning/memory neurons [26, 42]. Likewise mimicking the human disease condition, dFMR1 null animals display macroorchidism and deficits in spermatogenesis, hyperactivity and circadian arrhythmicity, and strong deficits in learning formation and memory consolidation [46, 83, 85, 87, 88, 92]. "
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome (FXS) is the most common known genetic form of intellectual disability and autism spectrum disorders. FXS patients suffer a broad range of other neurological symptoms, including hyperactivity, disrupted circadian activity cycles, obsessive-compulsive behavior, and childhood seizures. The high incidence and devastating effects of this disease state make finding effective pharmacological treatments imperative. Recently, reports in both mouse and Drosophila FXS disease models have indicated that the tetracycline derivative minocycline may hold great therapeutic promise for FXS patients. Both models strongly suggest that minocycline acts on the FXS disease state via inhibition of matrix metalloproteinases (MMPs), a class of zinc-dependent extracellular proteases important in tissue remodeling and cell-cell signaling. Recent FXS clinical trials indicate that minocycline may be effective in treating human patients. In this paper, we summarize the recent studies in Drosophila and mouse FXS disease models and human FXS patients, which indicate that minocycline may be an effective FXS therapeutic treatment, and discuss the data forming the basis for the proposed minocycline mechanism of action as an MMP inhibitor.
"Mouse and Drosophila melanogaster are the main genetic model organisms used to these purposes. The mouse Fmr1 gene and its two related genes Fxr1 and Fxr2 are well conserved relative to their human homologs FMR1, FXR1 and FXR2, respectively (Bakker et al., 1994; Bontekoe et al., 2002; Mientjes et al., 2004), whereas the fly model organism has a single FMR1 homolog (dFmr1) that is more functionally similar to human FMRP than to human FXR1 or FXR2 (Coffee et al., 2010). Both the fly and the mouse models present phenotypic abnormalities that are similar to those observed in humans such as: behavioural changes, altered axon morphology and connectivity, social, memory and learning deficits. "
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