Loading...
Thumbnail Image
Publication

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

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.
... show 1 more
Embargo Expiration Date
Link to Full Text
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

Year of Medical School at Time of Visit
Sponsors
Dates of Travel
DOI
10.1371/journal.pgen.1002515
PubMed ID
22347817
Other Identifiers
Notes
Funding and Acknowledgements
Corresponding Author
Related Resources
Related Resources
Repository Citation
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>
Distribution License