Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Ludwigstraße 43, 61231 Bad Nauheim, Germany.
Institute of Biochemistry, University of Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany.
Dev Cell. 2014 Oct 13;31(1):87-99. doi: 10.1016/j.devcel.2014.08.025.
Cell-type-specific splicing generates numerous alternatively spliced transcripts playing important roles for organ development and homeostasis, but only a few tissue-specific splicing factors have been identified. We found that RBM24 governs a large number of muscle-specific splicing events that are critically involved in cardiac and skeletal muscle development and disease. Targeted inactivation of RBM24 in mice disrupted cardiac development and impaired sarcomerogenesis in striated muscles. In vitro splicing assays revealed that recombinant RBM24 is sufficient to promote muscle-specific exon inclusion in nuclear extracts of nonmuscle cells. Furthermore, we demonstrate that binding of RBM24 to an intronic splicing enhancer (ISE) is essential and sufficient to overcome repression of exon inclusion by an exonic splicing silencer (ESS) containing PTB and hnRNP A1/A2 binding sites. Introduction of ESS and ISE converted a constitutive exon into an RMB24-dependent alternative exon. We reason that RBM24 is a major regulator of alternative splicing in striated muscles.
细胞类型特异性剪接产生了许多具有重要器官发育和稳态功能的选择性剪接转录本，但只有少数组织特异性剪接因子被鉴定出来。我们发现 RBM24 调控大量肌肉特异性剪接事件，这些事件对于心脏和骨骼肌的发育和疾病至关重要。在小鼠中靶向敲除 RBM24 会破坏心脏发育，并损害横纹肌中的肌节发生。体外剪接实验表明，重组 RBM24 足以促进非肌肉细胞核提取物中的肌肉特异性外显子包含。此外，我们证明 RBM24 与内含子剪接增强子（ISE）的结合对于克服含有 PTB 和 hnRNP A1/A2 结合位点的外显子剪接沉默子（ESS）对外显子包含的抑制作用是必需和充分的。引入 ESS 和 ISE 将一个组成性外显子转化为 RMB24 依赖性选择性外显子。我们推断 RBM24 是横纹肌中选择性剪接的主要调节剂。
