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Yao, A., Jin, S., Li, X., Liu, Z., Ma, X., Tang, J., Zhang, Y.Q. (2011). Drosophila FMRP regulates microtubule network formation and axonal transport of mitochondria.  Hum. Mol. Genet. 20(1): 51--63.
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Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein FMRP. The RNA-binding FMRP represses translation of the microtubule (MT)-associated protein 1B (MAP1B) during synaptogenesis in the brain of the neonatal mouse. However, the effect of FMRP on MTs remains unclear. Mounting evidence shows that the structure and the function of FMRP are well conserved across species from Drosophila to human. From a genetic screen, we identified spastin as a dominant suppressor of rough eye caused by dfmr1 over-expression. spastin encodes an MT-severing protein, and its mutations cause neurodegenerative hereditary spastic paraplegia. Epistatic and biochemical analyses revealed that dfmr1 acts upstream of or in parallel with spastin in multiple processes, including synapse development, locomotive behaviour and MT network formation. Immunostaining showed that both loss- and gain-of-function mutations of dfmr1 result in an apparently altered MT network. Western analysis revealed that the levels of α-tubulin and acetylated MTs remained normal in dfmr1 mutants, but increased significantly when dfmr1 was over-expressed. To examine the consequence of the aberrant MTs in dfmr1 mutants, we analysed the MT-dependent mitochondrial transport and found that the number of mitochondria and the flux of mitochondrial transport are negatively regulated by dfmr1. These results demonstrate that dFMRP plays a crucial role in controlling MT formation and mitochondrial transport. Thus, defective MTs and abnormal mitochondrial transport might account for, at least partially, the pathogenesis of fragile X mental retardation.

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    Hum. Mol. Genet.
    Human Molecular Genetics
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    Aberrations (1)
    Alleles (16)
    Genes (4)
    Human Disease Models (1)
    Insertions (3)
    Transgenic Constructs (9)