Today, heart failure remains a serious global health challenge. It affects more than 6.2 million people in the United States according to the 2019 data and this number is predicted to reach over 8 million by 2030. The ontology of heart failure involves a pathological process termed adverse remodelling, which is defined by cardiomyocyte hypertrophy and fibrosis. In the current issue of Acta Physiologica, Wang's group reported a novel signalling cascade from Mog1 to tbx5‐cryab/hspb2 whose disruption contributes to cardiac hypertrophy and heart failure.

Wang's group explored the in vivo phenotype of mog1 knockout (KO) using two lines of homozygous mog1 KO zebrafish.¹ MOG1 (human Ran guanine nucleotide release factor RANGNRF) is a small protein that binds to Ran and regulates the cytoplasm‐nucleus transportation of RNA and proteins. Recent genetic studies have identified several mutant alleles of MOG1 including p. E83D and p. E61X, associated with loss of function in the sodium current. Despite its known association in arrhythmia syndrome and heart failure, MOG1’s in vivo physiological function had not been discovered. In the mog1 KO zebrafish embryos, pericardial oedema together with enhanced expression of nppa were observed. Adult mog1 KO zebrafish exhibited significantly reduced ejection fraction (EF) and thickened ventricular wall, suggesting the onset of cardiac hypertrophy and heart failure. Upon isoproterenol (ISO) treatment, more severe phenotypes of cardiac hypertrophy and heart failure were observed in mog1 KO zebrafish at both the embryonic and adult stage. Thus, the paper for the first time demonstrated MOG1's role in in vivo physiological functions in cardiac morphogenesis, cardiac hypertrophy and heart failure.

Another highlight of the study is the establishment of a novel signalling cascade from Mog1 to tbx5‐cryab/hspb2. Previous cell culture studies conducted by Wang's group have demonstrated that MOG1 interacts with the voltage‐gated cardiac sodium channel Nav1.5, and further promotes Nav1.5 intracellular trafficking from endoplasmic reticulum to plasma membranes.² Mutation of the SCN5A gene that encodes Nav1.5 is reported to cause hereditary cardiac arrhythmias including Brugada syndrome (BrS).³ However, cell surface scn5a expression and sodium current densities were unchanged in the mog1 KO zebrafish heart, contrary to the association between MOG1 dosage and cell surface expression of Nav1.5 that had been noted in various cultured mammalian cells. This conflict might be explained by a genetic compensation response in gene KO zebrafish. In the current paper, a novel Mog1 hierarchy involving tbx5‐cryab‐hspb2 is reported. Identified by RNA‐seq and validated by RT‐PCR, the Mog1 dependant expressions of tbx5, cryab and hspb2 placed these genes downstream of Mog1. Although it is unknown by what mechanism Mog1 affects tbx5b expression, co‐transfection of Mog1 and Tbx5 significantly enhanced luciferase activity when binding to the cryab or hspb2 promoter regions. This indicated that cryab and hspb2 are downstream tagerts of Tbx5. Thus, a TBX5 consensus binding motif was suggested. However, to be proven, confirmation assays such as a luciferase reporter assay with site‐specific mutations are further needed. Importantly, overexpression of cryab and hspb2 partially rescued the pericardial oedema caused by Mog1 deletion. Taken together, these results established tbx5‐cryab‐hspb2 to be downstream of Mog1. Both CRYAB and HSPB2 are highly expressed in the human heart. Although their molecular functions remain unclear, CRYAB has been suggested to be involved in Calcineurin/NFAT signaling, and cytochrome c realease, which then affect the Ca²⁺/Na⁺ exchange and cardiomyocyte survival.

Various cardiac phenotypes—including cardiac hypertrophy, heart failure, abnormal cardiac morphogenesis and development—suggest that Mog1 is required in various molecular pathways for normal cardiac development and physiological function. In human, haploinsufficiency of TBX5 causes Holt‐Oram syndrome, manifested by congenital heart defects, conduction‐system abnormalities and upper‐limb deformities. In a Tbx5 KO zebrafish model, Deborah et al reported slow heart rate, which contributes to progressive stretching into a non‐functional heart.⁴ A harmonious activity of Nkx2‐5 and Tbx5 is required for the development of cardiac electrophysiological system.^{5, 6} Tbx5 mutant mice fail to develop a mature conduction system which results in atrioventricular node maturation failure, patterning defects of the ventricular bundle branches, and electrocardiographic abnormalities.⁵ In addition to reduced ejection fraction (EF) and thickened ventricular wall, the mog1 KO zebrafish had slow heart rate, along with elongated RR interval, QRS duration and QTc. Considering the important role of Tbx5 in the development of cardiac conduction system, some electrocardiographic abnormalities might be due to a congenital conduction system defect caused by tbx5 disruption during development, which further promotes the development and progression of heart failture later in life. In addition, mog1 KO zebrafish also display pericardial oedema and severe defects in cardiac looping, both associated with high mortality rates. The expression of multiple important transcription factors required for heart development, such as tbx5, nkx2.5, gata4 and hand2 was also significantly downregulated in mog1 KO zebrafish. Despite surgical correction, patients with cardiac abnormalities carry a life‐long risk for cardiovascular complications, and thus are at high risk for heart failure with an incidence up to 70% in selected populations. Various cardiac abnormalities that develop during embryonic stages potentiate and promote the progression of heart failure in adulthood. Thus, rather than direct prevention for heart failure, the novel signalling network from Mog1 to tbx5‐cryab/hspb2 may contribute to the heart development, which likely includes the maturation of cardiac electrophysiology.

It is not yet clarified how tbx5 downstream genes, cryab and hspb2, are involved in cardiac development during embryogenesis nor in heart failure development during adulthood. Although overexpression of cryabb and hspb2 partially rescued the pericardial oedema in mog1 KO zebrafish, its efficacy in rescuing electrophysiological abnormalities and preventing isoproterenol (ISO)‐induced heart failure remains to be investigated. Therefore, the functional signalling from tbx5 to cryabb and hspb2 contributing to heart development and rhythm maintenance still has much to uncover. Nonetheless, the study revealed a novel molecular mechanism involving tbx5 in which mog1 KO causes cardiac hypertrophy and heart failure.

As pointed out by the authors, one limitation of the study is that they do not address the molecular mechanism by which mog1 regulates tbx5 expression. Mog1 is a known coordinator of the Ran‐GTP cycle by binding to small GTPase Ran. The classic function of Ran is to regulate the cycle of nuclear import and export, which connects the nuclear transcription to the cytoplasmic translation of proteins. The predominant form of Ran in the nucleus is bound to GTP, while in the cytoplasm it is bound to GDP. Ran‐GTP binding to importins promotes cargo release, while binding to exportins stabilizes the exportin‐cargo interaction. In mitosis, the Ran‐GTP gradient around chromosomes restricts the activity of several spindle assembly factors, which then regulate the spindle assembly and cell division. MOG1 controls the Ran‐GTP cycle by stimulating the release of GTP from Ran‐GTP and remaining bound to nucleotide‐free Ran. Therefore, deleting Mog1 results in defective nuclear‐protein import. It is possible that Mog1 affects TBX5 level by regulating its transportation from the nucleus to the cytoplasm. To be noted, a recent study by Oliete‐Calvo et al suggests that Mog1 affects RNA transcription via epigenetic regulation. MOG1 is required for the H2B ubiquitination, which further determines the downstream histone H3 methylation, transcription and mRNA export.⁷ The mog1 KO study by Wang's group observed mRNA level changes of multiple transcription factors including tbx5, nkx2.5, gata4 and hand2, suggesting that the transcriptional regulation under mog1 may be at the whole genome level rather than at specific genomic regions. Future studies are needed to answer this important question: what molecular mechanism does mog1 alter to regulate the expressions of tbx5 and other transcription factors?

While questions remain, the new finding of the Wang group offers a novel working model for understanding cardiomyocyte hypertrophy and heart failure that Mog1 to tbx5‐cryab/hspb2 signalling is both developmentally required and physiologically relevant. The present study provides an important starting point to understand both, although translation of these findings to humans will need critical work performed on additional models.

如今，心力衰竭仍然是全球健康面临的严峻挑战。根据2019年的数据，它影响了美国620万人，到2030年，这一数字预计将超过800万人。心力衰竭的本体论涉及一种称为不良重塑的病理过程，其定义为心肌细胞肥大和纤维化。在最新一期《生理学报》中，Wang的研究小组报告了从Mog1到tbx5-cryab / hspb2的新型信号转导，其破坏会导致心脏肥大和心力衰竭。

Wang的小组使用两系纯合的mog1 KO斑马鱼探索了mog1基因敲除（KO）的体内表型。¹ MOG1（人类Ran鸟嘌呤核苷酸释放因子RANGNRF）是一种小蛋白，与Ran结合并调节RNA和蛋白质的细胞质-核转运。最近的遗传研究已经确定了MOG1的几个突变等位基因，包括p。E83D和p。E61X，与钠电流的功能丧失有关。尽管已知其与心律失常综合征和心力衰竭有关，但尚未发现MOG1的体内生理功能。在mog1 KO斑马鱼胚胎中，心包水肿和nppa表达增强被观察。成年mog1 KO斑马鱼表现出明显降低的射血分数（EF）和增厚的心室壁，提示心脏肥大和心力衰竭的发作。异丙肾上腺素（ISO）处理后，mog1 KO斑马鱼在胚胎期和成年期都观察到了心脏肥大和心力衰竭的更严重的表型。因此，该论文首次证明了MOG1在心脏形态发生，心脏肥大和心力衰竭的体内生理功能中的作用。

这项研究的另一个亮点是建立了从Mog1到tbx5-cryab / hspb2的新型信号级联。Wang小组先前进行的细胞培养研究表明，MOG1与电压门控性心脏钠通道Nav1.5相互作用，并进一步促进Nav1.5从内质网到质膜的细胞内运输。²据报道，编码Nav1.5的SCN5A基因突变导致遗传性心律失常，包括Brugada综合征（BrS）。³然而，mog1 KO斑马鱼心脏中的细胞表面scn5a表达和钠电流密度没有变化，这与在各种培养的哺乳动物细胞中已注意到Nav1.5的MOG1剂量和细胞表面表达。KO斑马鱼的遗传补偿反应可以解释这种冲突。在当前的论文中，报道了涉及tbx5-cryab-hspb2的新颖Mog1层次结构。通过RNA-seq鉴定并通过RT-PCR验证，tbx5，cryab和hspb2的Mog1依赖性表达将这些基因置于Mog1的下游。尽管尚不清楚Mog1通过哪种机制影响tbx5b的表达，但Mog1和Tbx5的共转染当与cryab或hspb2启动子区域结合时，荧光素酶活性显着增强。这表明cryab和hspb2是Tbx5的下游标签。因此，提出了TBX5共有结合基序。但是，要证明这一点，还需要进一步的确认分析，例如具有位点特异性突变的荧光素酶报告基因分析。重要的是，cryab和hspb2的过表达部分挽救了Mog1缺失引起的心包水肿。综上所述，这些结果确定tbx5-cryab-hspb2位于Mog1的下游。CRYAB和HSPB2在人类心脏中都高度表达。尽管尚不清楚它们的分子功能，但已建议CRYAB参与钙调神经磷酸酶/ NFAT信号传导和细胞色素c释放酶，然后影响Ca ²⁺ / Na ⁺交换和心肌细胞存活。

各种心脏表型，包括心脏肥大，心力衰竭，异常的心脏形态发生和发展，建议在正常的心脏发育和生理功能的各种分子途径中都需要Mog1。在人类中，TBX5的单倍剂量不足会导致Holt-Oram综合征，表现为先天性心脏缺陷，传导系统异常和上肢畸形。在Tbx5 KO斑马鱼模型中，Deborah等人报道了心律缓慢，这有助于逐步向无功能的心脏伸展。⁴心脏电生理系统的发育需要Nkx2-5和Tbx5的协调活性。^5，6 汤匙x5突变小鼠无法形成成熟的传导系统，从而导致房室结成熟失败，心室束支的构图缺陷和心电图异常。⁵除了减少射血分数（EF）和增加心室壁，mog1 KO斑马鱼的心律缓慢，RR间隔，QRS持续时间和QTc延长。考虑到Tbx5在心脏传导系统发育中的重要作用，某些心电图异常可能是由于发育期间tbx5破坏引起的先天性传导系统缺陷所致，这进一步促进了心脏衰竭的发展和发展。另外，mog1KO斑马鱼还表现出心包水肿和心脏循环不良的严重缺陷，两者均与高死亡率相关。对心脏发育所需的多个重要的转录因子，如表达TBX5，NKX2.5，GATA4和HAND2也显著下调中mog1KO斑马鱼。尽管进行了外科手术矫正，心脏异常患者仍终生罹患心血管并发症，因此心衰风险很高，在某些人群中发生率高达70％。在胚胎期发展的各种心脏异常会增强并促进成年后心力衰竭的发展。因此，不是直接预防心力衰竭，而是从Mog1到tbx5-cryab / hspb2的新型信号网络可能有助于心脏发育，其中可能包括心脏电生理学的成熟。

尚不清楚tbx5下游基因cryab和hspb2如何参与胚胎发生期间的心脏发育或成年期间的心力衰竭发展。尽管cryabb和hspb2的过表达部分缓解了mog1 KO斑马鱼的心包水肿，但其在挽救电生理异常和预防异丙肾上腺素（ISO）引起的心力衰竭中的功效仍有待研究。因此，从tbx5到cryabb和hspb2的功能性信号传导有助于心脏发育和节律维持的事情还有很多。尽管如此，该研究揭示了涉及tbx5的新型分子机制，其中mog1 KO引起心脏肥大和心力衰竭。

正如作者所指出的那样，这项研究的局限性在于它们没有解决mog1调节tbx5的分子机制。表达。Mog1通过与小GTPase Ran结合而成为Ran-GTP周期的已知协调员。Ran的经典功能是调节核进出口的循环，从而将核转录与蛋白质的胞质翻译联系起来。Ran在细胞核中的主要形式与GTP结合，而在细胞质中它与GDP结合。Ran-GTP与importins的结合促进了货物的释放，而与exportins的结合则稳定了exportin-Cargo的相互作用。在有丝分裂中，染色体周围的Ran-GTP梯度限制了几个纺锤体组装因子的活性，从而调节了纺锤体组装和细胞分裂。MOG1通过刺激Ran-GTP释放GTP并保持与无核苷酸Ran的结合来控制Ran-GTP周期。因此，删除Mog1会导致有缺陷的核蛋白输入。Mog1通过调节TBX5从细胞核到细胞质的转运来影响TBX5的水平。值得注意的是，Oliete-Calvo等人的最新研究表明，Mog1通过表观遗传调控影响RNA转录。H2B泛素化需要MOG1，这进一步决定了下游组蛋白H3甲基化，转录和mRNA输出。⁷ Wang小组的mog1 KO研究观察到tbx5，nkx2.5，gata4和hand2等多种转录因子的mRNA水平变化，表明mog1的转录调控可能在整个基因组水平，而不是在特定的基因组区域。需要进一步的研究来回答这个重要的问题：mog1会改变哪些分子机制来调节tbx5和其他转录因子的表达？

尽管仍然存在疑问，但Wang组的新发现为理解心肌肥大和心力衰竭提供了一个新颖的工作模型，Mog1至tbx5-cryab / hspb2信号是发展所必需的，并且与生理相关。尽管将这些发现转化为人类将需要在其他模型上进行关键的工作，但本研究为理解两者提供了重要的起点。