Abstract
MOG1 was initially identified as a protein that interacts with the small GTPase Ran involved in transport of macromolecules into and out of the nucleus. In addition, we have established that MOG1 interacts with the cardiac sodium channel Nav1.5 and regulates cell surface trafficking of Nav1.5. Here we used zebrafish as a model system to study the in vivo physiological role of MOG1. Knockdown of mog1 expression in zebrafish embryos significantly decreased the heart rate (HR). Consistently, the HR increases in embryos with over-expression of human MOG1. Compared with wild type MOG1 or control EGFP, mutant MOG1 with mutation E83D associated with Brugada syndrome significantly decreases the HR. Interestingly, knockdown of mog1 resulted in abnormal cardiac looping during embryogenesis. Mechanistically, knockdown of mog1 decreases expression of hcn4 involved in the regulation of the HR, and reduces expression of nkx2.5, gata4 and hand2 involved in cardiac morphogenesis. These data for the first time revealed a novel role that MOG1, a nucleocytoplasmic transport protein, plays in cardiac physiology and development.
Highlights
MOG1 was initially cloned from Saccharomyces cerevisiae while screening for a multi-copy suppressor of conditional growth defect alleles of the Ran gene (GSP1)[1]
We have identified the first series of mutations in SCN5A which cause inherited cardiac arrhythmias and sudden death in the young, otherwise healthy, individuals, including long QT syndrome (LQTS) and Brugada syndrome (BrS)[6,12,13]
Similar results were obtained with mog[1] MO2 (Fig. 5E,F), the effect of MO2 was less severe than that of MO1. These results suggest that mog[1] plays an important role in heart development during embryogenesis
Summary
MOG1 was initially cloned from Saccharomyces cerevisiae while screening for a multi-copy suppressor of conditional growth defect alleles of the Ran gene (GSP1) ( named as mog1)[1]. Human MOG1 protein was shown to interact directly with Ran, too, and could partially rescue the growth defects of Δ MOG1 yeast cells. During a yeast two-hybrid screen, we identified MOG1 as a protein that interacts directly with the voltage-gated cardiac sodium channel Nav1.55. MOG1, delivered by gene therapy, may be used as an effective tool to treat patients with BrS and sick sinus syndrome with SCN5A/Nav1.5 mutations and other cardiac diseases with reduced INa. Despite the important roles of MOG1 in human diseases and potential utility in treating lethal arrhythmias, little is known about the in vivo function of MOG1. Cardiac precursors are located at the blastula margin, and development of the zebrafish heart begins at 5 hours post fertilization (hpf)[19]. We found that Mog[1] regulates the heart rate during embryogenesis by regulating the expression of ion channel gene hcn[4]
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