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    Neurophysiological defects and neuronal gene deregulation in Drosophila mir-124 mutants

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    Authors
    Sun, Kailiang
    Westholm, Jakub Orzechowski
    Tsurudome, Kazuya
    Hagen, Joshua W
    Lu, Yubing
    Kohwi, Minoree
    Betel, Doron
    Gao, Fen-Biao
    Haghighi, A. Pejmun
    Doe, Chris Q.
    Lai, Eric C.
    Show allShow less
    UMass Chan Affiliations
    Department of Neurology
    Document Type
    Journal Article
    Publication Date
    2012-02-09
    Keywords
    Animals
    Cell Differentiation
    Drosophila melanogaster
    Gene Expression Regulation, Developmental
    Gene Knockout Techniques
    Locomotion
    MicroRNAs
    Mutation
    Neurogenesis
    Neuromuscular Junction
    Phenotype
    Sensory Receptor Cells
    Signal Transduction
    Synapses
    Transcriptome
    Neurology
    Neuroscience and Neurobiology
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    Abstract
    miR-124 is conserved in sequence and neuronal expression across the animal kingdom and is predicted to have hundreds of mRNA targets. Diverse defects in neural development and function were reported from miR-124 antisense studies in vertebrates, but a nematode knockout of mir-124 surprisingly lacked detectable phenotypes. To provide genetic insight from Drosophila, we deleted its single mir-124 locus and found that it is dispensable for gross aspects of neural specification and differentiation. On the other hand, we detected a variety of mutant phenotypes that were rescuable by a mir-124 genomic transgene, including short lifespan, increased dendrite variation, impaired larval locomotion, and aberrant synaptic release at the NMJ. These phenotypes reflect extensive requirements of miR-124 even under optimal culture conditions. Comparison of the transcriptomes of cells from wild-type and mir-124 mutant animals, purified on the basis of mir-124 promoter activity, revealed broad upregulation of direct miR-124 targets. However, in contrast to the proposed mutual exclusion model for miR-124 function, its functional targets were relatively highly expressed in miR-124-expressing cells and were not enriched in genes annotated with epidermal expression. A notable aspect of the direct miR-124 network was coordinate targeting of five positive components in the retrograde BMP signaling pathway, whose activation in neurons increases synaptic release at the NMJ, similar to mir-124 mutants. Derepression of the direct miR-124 target network also had many secondary effects, including over-activity of other post-transcriptional repressors and a net incomplete transition from a neuroblast to a neuronal gene expression signature. Altogether, these studies demonstrate complex consequences of miR-124 loss on neural gene expression and neurophysiology.
    Source
    Sun K, Westholm JO, Tsurudome K, Hagen JW, Lu Y, et al. (2012) Neurophysiological Defects and Neuronal Gene Deregulation in Drosophila mir-124 Mutants. PLoS Genet 8(2): e1002515. doi:10.1371/journal.pgen.1002515. Link to article on publisher's site
    DOI
    10.1371/journal.pgen.1002515
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/37737
    PubMed ID
    22347817
    Related Resources
    Link to Article in PubMed
    Rights

    Copyright: © 2012 Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    10.1371/journal.pgen.1002515
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