mRNA processing is highly regulated during development through changes in RNA-binding protein (RBP) activities. CUG-BP, Elav-like family member 1 (CELF1, also called CUGBP1) is an RBP, the expression of which decreases in skeletal muscle soon after birth. CELF1 regulates multiple nuclear and cytoplasmic RNA processing events. In the nucleus, CELF1 regulates networks of postnatal alternative splicing (AS) transitions, while in the cytoplasm, CELF1 regulates mRNA stability and translation. Stabilization and misregulation of CELF1 has been implicated in human diseases including myotonic dystrophy type 1, Alzheimer’s disease and multiple cancers. To understand the contribution of nuclear and cytoplasmic CELF1 activity to normal and pathogenic skeletal muscle biology, we generated transgenic mice for doxycycline-inducible and skeletal muscle-specific expression of active CELF1 mutants engineered to be localized predominantly to either the nucleus or the cytoplasm. Adult mice expressing nuclear, but not cytoplasmic, CELF1 are characterized by strong histopathological defects, muscle loss within 10 days and changes in AS. In contrast, mice expressing cytoplasmic CELF1 display changes in protein levels of targets known to be regulated at the level of translation by CELF1, with minimal changes in AS. These changes are in the absence of overt histopathological changes or muscle loss. RNA-sequencing revealed extensive gene expression and AS changes in mice overexpressing nuclear and naturally localized CELF1 protein, with affected genes involved in cytoskeleton dynamics, membrane dynamics, RNA processing and zinc ion binding. These results support a stronger role for nuclear CELF1 functions as compared to cytoplasmic CELF1 functions in skeletal muscle wasting.

中文翻译：

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CELF1 蛋白的核活性增加，但细胞质活性增加，导致肌肉萎缩。


mRNA 加工在发育过程中通过 RNA 结合蛋白 (RBP) 活性的变化受到高度调控。 CUG-BP，Elav 样家族成员 1（CELF1，也称为 CUGBP1）是一种 RBP，其表达在出生后不久在骨骼肌中减少。 CELF1 调节多个核和细胞质 RNA 加工事件。在细胞核中，CELF1 调节出生后选择性剪接 (AS) 转换网络，而在细胞质中，CELF1 调节 mRNA 稳定性和翻译。 CELF1 的稳定和失调与人类疾病有关，包括 1 型强直性肌营养不良、阿尔茨海默病和多种癌症。为了了解细胞核和细胞质 CELF1 活性对正常和致病性骨骼肌生物学的贡献，我们培育了转基因小鼠，用于多西环素诱导和骨骼肌特异性表达活性 CELF1 突变体，这些突变体被设计为主要定位于细胞核或细胞质。表达细胞核但不表达细胞质的 CELF1 成年小鼠的特点是强烈的组织病理学缺陷、10 天内肌肉损失和 AS 变化。相比之下，表达细胞质CELF1的小鼠表现出已知在翻译水平上受CELF1调节的靶标的蛋白质水平的变化，而AS的变化最小。这些变化是在没有明显的组织病理学变化或肌肉损失的情况下发生的。 RNA测序揭示了过度表达细胞核和自然定位的CELF1蛋白的小鼠中广泛的基因表达和AS变化，受影响的基因涉及细胞骨架动力学、膜动力学、RNA加工和锌离子结合。这些结果支持与细胞质 CELF1 功能相比，细胞核 CELF1 功能在骨骼肌消耗中发挥更强的作用。