Mutation of Rubie, a Novel Long Non-Coding RNA Located Upstream of Bmp4, Causes Vestibular Malformation in Mice

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Mutation of Rubie, a Novel Long Non-Coding RNA Located Upstream of Bmp4, Causes Vestibular Malformation in Mice

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dc.contributor.author Roberts, Kristina A.
dc.contributor.author Abraira, Victoria E.
dc.contributor.author Tucker, Andrew F.
dc.contributor.author Andrews, Nancy C.
dc.contributor.author Goodrich, Lisa V.
dc.date.accessioned 2012-05-08T21:29:57Z
dc.date.issued 2012
dc.identifier.citation Roberts, Kristina A., Victoria E. Abraira, Andrew F. Tucker, Lisa V. Goodrich, and Nancy C. Andrews. 2012. Mutation of rubie, a novel long non-coding rna located upstream of bmp4, causes vestibular malformation in mice. PLoS ONE 7(1): e29495. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8701028
dc.description.abstract Background: The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified. Methodology/Principal Findings We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears. Conclusions/Significance: Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0029495 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257225/pdf/ en_US
dash.license LAA
dc.title Mutation of Rubie, a Novel Long Non-Coding RNA Located Upstream of Bmp4, Causes Vestibular Malformation in Mice en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Goodrich, Lisa V.
dc.date.available 2012-05-08T21:29:57Z

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