ABSTRACT

Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.

摘要

组织特异性选择性剪接 (AS) 正在成为与器官发育和疾病相关的最令人兴奋的机制类型之一。在听觉系统中，许多与听力相关的基因发生AS，这个过程中的错误导致综合征性或非综合征性听力损失。然而，关于在内耳中引导 AS 的因素和机制知之甚少。在本研究中，我们鉴定了一种新的 RNA 结合蛋白 Rbm24，它与调节内耳特异性 AS 密切相关。Rbm24 缺失导致听力损失和运动协调缺陷。全局剪接分析显示 Rbm24 是正确剪接前 mRNA 转录本子集所必需的，这些转录本在毛细胞静纤毛完整性和存活中起重要作用。此外，我们发现 Rbm24 直接调节 Cdh23 的剪接，一种导致人类亚瑟综合征 1D 和非综合征常染色体隐性耳聋 DFNB12 的已知疾病基因。总之，我们的研究结果表明 Rbm24 是调节内耳特异性剪接和维持内耳听力和运动协调功能的关键因素。我们的数据不仅提供了机械见解，而且还提供了导致听力损失的 Rbm24 剪接目标的功能注释。