Calreticulin deficiency causes myocardial developmental defects that culminate in an embryonic lethal phenotype. Recent studies have linked loss of this calcium binding chaperone to failure in myofibrillogenesis through an as yet undefined mechanism. The purpose of the present study was to identify cellular processes corrupted by calreticulin deficiency that precipitate dysregulation of cardiac myofibrillogenesis related to acquisition of cardiac phenotype. In an embryonic stem cell knockout model, calreticulin deficit (crt(-/-)) compromised nucleocytoplasmic transport of nuclear localization signal-dependent and independent pathways, disrupting nuclear import of the cardiac transcription factor MEF2C. The expression of nucleoporins and associated nuclear transport proteins in derived crt(-/-) cardiomyocytes revealed an abnormal nuclear pore complex (NPC) configuration. Altered protein content in crt(-/-) cells resulted in remodeled NPC architecture that caused decreased pore diameter and diminished probability of central channel occupancy versus wild type counterparts. Ionophore treatment of impaired calcium handling in crt(-/-) cells corrected nuclear pore microarchitecture and rescued nuclear import resulting in normalized myofibrillogenesis. Thus, calreticulin deficiency alters nuclear pore function and structure, impeding myofibrillogenesis in nascent cardiomyocytes through a calcium dependent mechanism. This essential role of calreticulin in nucleocytoplasmic communication competency ties its regulatory action with proficiency of cardiac myofibrillogenesis essential for proper cardiac development.

中文翻译：

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钙网蛋白可确保心脏发生所需的钙依赖性核孔功能。

钙网蛋白缺乏导致心肌发育缺陷，最终导致胚胎致死表型。最近的研究已经通过尚未确定的机制将这种钙结合伴侣的丧失与肌原纤维形成的失败联系起来。本研究的目的是确定因钙网蛋白缺乏而受损的细胞过程，该过程会导致与心脏表型获得有关的心肌肌纤维生成异常。在胚胎干细胞基因敲除模型中，钙网蛋白缺陷（crt（-/-））破坏了核定位信号依赖和独立途径的核质运输，破坏了心脏转录因子MEF2C的核输入。核蛋白和相关的核转运蛋白在衍生的crt（-/-）心肌细胞中的表达揭示了异常的核孔复合体（NPC）配置。与野生型对应物相比，crt（-/-）细胞中蛋白质含量的变化导致NPC结构的改型，从而导致孔径减小和中央通道占用率降低。离子载体治疗crt（-/-）细胞中钙处理受损的现象可纠正核孔微结构并拯救核输入，从而使肌原纤维形成正常化。因此，钙网蛋白缺乏会改变核孔的功能和结构，从而通过钙依赖性机制阻碍新生心肌细胞的肌原纤维形成。