Vertebrate skeletal muscle development and repair relies on the precise control of Wnt signaling. Dact1 (Dapper/Frodo) is an important modulator of Wnt signaling, interacting with key components of the various Wnt transduction pathways. Here, we characterized Dact1 mRNA and protein expression in chicken and mouse fetal muscles in vivo and during the differentiation of chick primary and mouse C2C12 myoblasts in vitro. We also performed in silico analysis to investigate Dact1 gene expression in human myopathies, and evaluated the Dact1 protein structure to seek an explanation for the accumulation of Dact1 protein aggregates in the nuclei of myogenic cells.

Our results show for the first time that in both chicken and mouse, Dact1 is expressed during myogenesis, with a strong upregulation as cells engage in terminal differentiation, cell cycle withdrawal and cell fusion. In humans, Dact1 expression was found to be altered in specific muscle pathologies, including muscular dystrophies. Our bioinformatic analyses of Dact1 proteins revealed long intrinsically disordered regions, which may underpin the ability of Dact1 to interact with its many partners in the various Wnt pathways. In addition, we found that Dact1 has strong propensity for liquid-liquid phase separation, a feature that explains its ability to form nuclear aggregates and points to a possible role as a molecular ‘on’-‘off’ switch.

Taken together, our data suggest Dact1 as a candidate, multi-faceted regulator of amniote myogenesis with a possible pathophysiological role in human muscular diseases.

脊椎动物骨骼肌的发育和修复依赖于 Wnt 信号的精确控制。Dact1 (Dapper/Frodo) 是 Wnt 信号传导的重要调节剂，与各种 Wnt 转导通路的关键成分相互作用。在这里，我们表征了体内鸡和小鼠胎儿肌肉中的Dact1 mRNA 和蛋白质表达，以及体外鸡原代和小鼠 C2C12 成肌细胞的分化过程。我们还进行了计算机分析以研究Dact1基因在人类肌病中的表达，并评估 Dact1 蛋白结构以寻求对 Dact1 蛋白聚集体在肌细胞核中积累的解释。

我们的结果首次表明，在鸡和小鼠中，Dact1在肌生成过程中表达，随着细胞参与终末分化、细胞周期退出和细胞融合，Dact1表达强烈上调。在人类中，发现Dact1表达在特定肌肉病理学中发生改变，包括肌营养不良症。我们对 Dact1 蛋白的生物信息学分析揭示了长期的内在无序区域，这可能支持 Dact1 与其在各种 Wnt 通路中的许多伙伴相互作用的能力。此外，我们发现 Dact1 具有很强的液-液相分离倾向，这一特征解释了其形成核聚集体的能力，并指出它可能作为分子“开”-“关”开关的作用。

总之，我们的数据表明 Dact1 是羊膜肌生成的候选多方面调节剂，在人类肌肉疾病中可能具有病理生理学作用。