Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse.
Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse.
复制标题
DOI：
10.26508/lsa.202000841
复制
发表时间：
2020-12
影响因子：
4.4
通讯作者：
Bánfi B
中科院分区：
文献类型：
--
作者：
Nakano Y;Wiechert S;Fritzsch B;Bánfi B
剪接因子SRRM 4在耳的前庭和内毛细胞中的重要作用是使基因阻遏物REST失活;然而，在外毛细胞中，SRRM 4被抑制REST失活，而SRRM 3独立完成REST失活。在耳的机械感觉毛细胞（HC）中，转录抑制因子REST通过其前体mRNA的选择性剪接而持续失活。这种REST失活机制对人类和小鼠的听力至关重要。Rest是许多前体mRNA之一，其选择性剪接受剪接因子SRRM 4调节;小鼠中的Srrm 4功能丧失突变（Srrm 4 bv/bv）导致耳聋，平衡缺陷和除外部HC（OHC）以外的所有HC类型的退化。在Srrm 4 bv/bv小鼠中驱动HC变性的特定剪接改变是未知的，并且OHC的SRRM 4独立存活的潜在机制是不确定的。在这里，我们表明，显性负性REST片段在Srrm 4 bv/bv小鼠的转基因表达是足够的长期救援的听力，平衡，HC，选择性剪接的休息，和表达的REST靶基因，包括Srrm 4 paradox Srrm 3。我们还表明，在HC中，SRRM 3调节许多与SRRM 4相同的外显子; OHC在HC中是独特的，因为它们在成熟时瞬时下调Rest转录以独立于SRRM 4表达Srrm 3;同时SRRM 4-SRRM 3缺陷通过防止所有HC中的REST失活而导致HC完全丧失。因此，我们的数据表明，REST失活是SRRM 4在耳中的主要和必不可少的作用，并且OHC与其他HC在SRRM 4独立表达功能SRRM 4样剪接因子SRRM 3方面不同。
The vital role of the splicing factor SRRM4 in vestibular and inner hair cells of the ear is inactivation of the gene repressor REST; however, in outer hair cells, SRRM4 is dispensable for REST inactivation, which SRRM3 accomplishes independently. In mechanosensory hair cells (HCs) of the ear, the transcriptional repressor REST is continuously inactivated by alternative splicing of its pre-mRNA. This mechanism of REST inactivation is crucial for hearing in humans and mice. Rest is one of many pre-mRNAs whose alternative splicing is regulated by the splicing factor SRRM4; Srrm4 loss-of-function mutation in mice (Srrm4bv/bv) causes deafness, balance defects, and degeneration of all HC types other than the outer HCs (OHCs). The specific splicing alterations that drive HC degeneration in Srrm4bv/bv mice are unknown, and the mechanism underlying SRRM4-independent survival of OHCs is undefined. Here, we show that transgenic expression of a dominant-negative REST fragment in Srrm4bv/bv mice is sufficient for long-term rescue of hearing, balancing, HCs, alternative splicing of Rest, and expression of REST target genes including the Srrm4 paralog Srrm3. We also show that in HCs, SRRM3 regulates many of the same exons as SRRM4; OHCs are unique among HCs in that they transiently down-regulate Rest transcription as they mature to express Srrm3 independently of SRRM4; and simultaneous SRRM4–SRRM3 deficiency causes complete HC loss by preventing inactivation of REST in all HCs. Thus, our data reveal that REST inactivation is the primary and essential role of SRRM4 in the ear, and that OHCs differ from other HCs in the SRRM4-independent expression of the functionally SRRM4-like splicing factor SRRM3.
登录
查看更多内容
影响因子：
4.4
作者：
Alagramam, Kumar N.;Miller, Nathaniel D.;Smith, Richard J.
通讯作者：
Smith, Richard J.
影响因子：
16.6
作者：
Isgrig, Kevin;McDougald, Devin S.;Chien, Wade W.
通讯作者：
Chien, Wade W.
影响因子：
3.5
作者：
Beisel, Kirk W.;Rocha-Sanchez, Sonia M.;Davis, Robin L.
通讯作者：
Davis, Robin L.
影响因子：
3.5
作者：
Boëda, B;Weil, D;Petit, C
通讯作者：
Petit, C
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ