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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  ( R NA  u pstream of   B mp4  expressed in  i nner  e ar).  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.

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