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dc.contributor.authorSun, Kailiang
dc.contributor.authorWestholm, Jakub Orzechowski
dc.contributor.authorTsurudome, Kazuya
dc.contributor.authorHagen, Joshua W
dc.contributor.authorLu, Yubing
dc.contributor.authorKohwi, Minoree
dc.contributor.authorBetel, Doron
dc.contributor.authorGao, Fen-Biao
dc.contributor.authorHaghighi, A. Pejmun
dc.contributor.authorDoe, Chris Q.
dc.contributor.authorLai, Eric C.
dc.date2022-08-11T08:09:28.000
dc.date.accessioned2022-08-23T16:31:48Z
dc.date.available2022-08-23T16:31:48Z
dc.date.issued2012-02-09
dc.date.submitted2012-09-12
dc.identifier.citationSun K, Westholm JO, Tsurudome K, Hagen JW, Lu Y, et al. (2012) Neurophysiological Defects and Neuronal Gene Deregulation in <em>Drosophila mir-124</em> Mutants. PLoS Genet 8(2): e1002515. doi:10.1371/journal.pgen.1002515. <a href="http://dx.doi.org/10.1371/journal.pgen.1002515" target="_blank">Link to article on publisher's site</a>
dc.identifier.issn1553-7390 (Linking)
dc.identifier.doi10.1371/journal.pgen.1002515
dc.identifier.pmid22347817
dc.identifier.urihttp://hdl.handle.net/20.500.14038/37737
dc.description.abstractmiR-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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22347817&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>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.</p>
dc.subjectAnimals
dc.subjectCell Differentiation
dc.subjectDrosophila melanogaster
dc.subjectGene Expression Regulation, Developmental
dc.subjectGene Knockout Techniques
dc.subjectLocomotion
dc.subjectMicroRNAs
dc.subjectMutation
dc.subjectNeurogenesis
dc.subjectNeuromuscular Junction
dc.subjectPhenotype
dc.subjectSensory Receptor Cells
dc.subjectSignal Transduction
dc.subjectSynapses
dc.subjectTranscriptome
dc.subjectNeurology
dc.subjectNeuroscience and Neurobiology
dc.titleNeurophysiological defects and neuronal gene deregulation in Drosophila mir-124 mutants
dc.typeJournal Article
dc.source.journaltitlePLoS genetics
dc.source.volume8
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1410&amp;context=neuro_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neuro_pp/411
dc.identifier.contextkey3316127
refterms.dateFOA2022-08-23T16:31:48Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathneuro_pp/411
dc.contributor.departmentDepartment of Neurology
dc.source.pagese1002515


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