Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.

中文翻译：

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运动神经元中的 MBNL 缺陷会破坏神经肌肉接头的维持和步态协调


肌盲样蛋白 （MBNL） 是一个 RNA 结合蛋白家族，在 RNA 代谢的调节中起着重要作用。除了在 RNA 调节中的经典作用外，MBNL 蛋白已成为 1 型强直性肌营养不良症 （DM1） 发病机制的关键参与者。在 DM1 中，通过 CUG 重复序列 RNA 的扩增隔离 MBNL 蛋白导致 MBNL 的功能耗竭，导致选择性剪接失调和 RNA 加工异常，这是该疾病临床特征的基础。虽然对 MBNL 蛋白的关注集中在它们在骨骼肌中的功能上，但新的证据表明，它们的重要性延伸到运动神经元 （MN），这是控制运动技能和运动的关键细胞成分。为了解决这个问题，我们生成了条件性双敲除小鼠，其中 Mbnl1 和 Mbnl2 在运动神经元 （MN-dKO） 中被特异性删除。成年 MN-dKO 小鼠出现与神经肌肉接头的结构和超微结构缺陷相关的步态协调缺陷，表明 MNs 中的 MBNL 活性对于神经肌肉接头的维持至关重要。此外，对 MN-dKO 小鼠脊髓进行的转录组分析确定了与突触传递和神经肌肉接头稳态相关的基因中的错误剪接事件。总之，我们的结果突出了 MBNL 蛋白在 MNs 中对肌肉功能和运动的复杂作用和调节机制。这项工作为 RNA 生物学的基本方面提供了有价值的见解，并为 DM1 的治疗干预以及与 RNA 失调相关的一系列疾病提供了有希望的途径。