Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice.
Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice.
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DOI：
10.1371/journal.pone.0029495
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Andrews NC
中科院分区：
文献类型：
--
作者：
Roberts KA;Abraira VE;Tucker AF;Goodrich LV;Andrews NC
脊椎动物内耳的前庭装置使用三个充满液体的半规管来感知头部的角加速度。这些管道的畸形会破坏小鼠的平衡感，并经常导致小鼠出现转圈行为。上位环 (Ecl) 是源自野生型 SWR/J 和 C57L/J 小鼠的复杂突变体。 Ecl 循环已被证明是由 14 号染色体上的 SWR 衍生基因座和 4 号染色体上的 C57L 衍生基因座的上位相互作用引起的，但之前尚未鉴定出致病基因。我们开发了一种小鼠染色体替代品系（CSS-14），它在 C57BL/10J 遗传背景上携带 SWR/J 14 号染色体，并且像 Ecl 一样，由于侧半规管畸形而表现出盘旋行为。我们利用 CSS-14 通过定位克隆鉴定了 14 号染色体 Ecl 基因。我们的候选区间位于骨形态发生蛋白 4 (Bmp4) 的上游，并且包含内耳特异性的长非编码 RNA，我们将其指定为 Rubie（在内耳中表达的 Bmp4 上游的 RNA）。 Rubie 被剪接和聚腺苷酸化，并在发育中的半规管中表达。然而，我们发现 Rubie 的 SWR/J 等位基因被内含子内源性逆转录病毒破坏，导致转录物异常剪接和过早多腺苷酸化。 Rubie 位于 Bmp4 上游的保守基因荒漠中，该区域先前显示对 Bmp4 的内耳表达很重要。我们发现 Bmp4 和 Rubie 在内耳发育过程中的表达模式几乎相同。基于这些结果和之前的研究表明 Bmp4 对于正常的前庭发育至关重要，我们提出 Rubie 是 Ecl 小鼠中突变的基因，它参与调节 Bmp4 的内耳表达，并且异常的 Bmp4 表达有助于 Ecl 表型。
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. 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. 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.
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影响因子：
4.5
作者：
Maksakova IA;Romanish MT;Gagnier L;Dunn CA;van de Lagemaat LN;Mager DL
通讯作者：
Mager DL
DOI：
10.1242/dev.029330
发表时间：
2008-12
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Abraira VE;Del Rio T;Tucker AF;Slonimsky J;Keirnes HL;Goodrich LV
通讯作者：
Goodrich LV
BMP4对于检测角头运动的前庭设备的形成至关重要。
影响因子：
4.5
作者：
Chang, Weise;Lin, Zhengshi;Kulessa, Holger;Hebert, Jean;Hogan, Brigid L. M.;Wu, Doris K.
通讯作者：
Wu, Doris K.
影响因子：
4.3
作者：
Dinger ME;Pang KC;Mercer TR;Mattick JS
通讯作者：
Mattick JS
影响因子：
16.2
作者：
Cowan, CA;Yokoyama, N;Fritzsch, B
通讯作者：
Fritzsch, B