Translational control of furina by an RNA regulon is essential for heart morphogenesis and cardiac valve function
Translational control of furina by an RNA regulon is essential for heart morphogenesis and cardiac valve function
复制标题
DOI：
10.1101/2023.01.30.526270
复制
发表时间：
2023-02
期刊：
影响因子：
--
通讯作者：
Agnieszka Nagorska;Finnlay R. P. Lambert;Angus Inman;Sara Toral-Perez;A. Zaucker;J. Gorodkin;Wan Yue;Michael Smutny;K. Sampath
中科院分区：
文献类型：
--
作者：
Agnieszka Nagorska;Finnlay R. P. Lambert;Angus Inman;Sara Toral-Perez;A. Zaucker;J. Gorodkin;Wan Yue;Michael Smutny;K. Sampath
心脏的发育是一个复杂的过程，从心脏前体的形成和线状管的形成，到逐渐发展成为一个功能性的跳动器官。对于正常的心脏发育，许多过程，包括心脏沿左/右（L/R）轴的不对称定位、心脏生长和心脏瓣膜形态发生必须成功完成。虽然心脏发育已被广泛研究，但控制心脏形态发生和瓣膜形成的机制尚不完全清楚。前转化酶FurinA是包括斑马鱼在内的许多脊椎动物心脏发育中起作用的关键蛋白质。在心脏发育过程中FurinA活性是如何被调节的尚不清楚。通过对斑马鱼转录组的计算分析，我们在FurinA的变体转录本中发现了一个短序列和结构RNA基序，其中包含一个长3 ‘非翻译区（3’UTR）。替代的3'UTR furina异构体在器官定位之前的胚胎阶段表达。报告定位和rna结合实验表明，furina 3'UTR与保守的rna结合蛋白和翻译抑制因子Ybx1形成复合物。影响ybx1的条件突变斑马鱼胚胎表现出早熟和Furin报告蛋白表达增加，心脏形态发生异常和心环缺陷。我们的突变型ybx1心脏有扩张的房室管，异常的心房瓣膜和许多突变胚胎显示逆行的血液从心室流向心房。这类似于人类心脏瓣膜返流患者。我们的研究结果表明，3'UTR元件/Ybx1调控在FurinA的翻译抑制中具有重要作用，揭示了控制胚胎心脏发育的新的上游调控机制，并证明了Ybx1突变体可以作为研究心脏瓣膜发育和功能的模型。
Heart development is a complex process, starting from specification of cardiac precursors and formation of a linear tube to gradual progression to a functional beating organ. For normal heart development, many processes, including asymmetric positioning of the heart along the left-right (L/R) axis, cardiac growth, and cardiac valve morphogenesis must be completed successfully. Although heart development has been studied extensively, the mechanisms that control heart morphogenesis and valve formation are not fully understood. The pro-convertase FurinA is a key protein that functions in heart development in many vertebrates including zebrafish. How FurinA activity is regulated during heart development is not known. Through computational analysis of the zebrafish transcriptome, we identified a short sequence and structure RNA motif in a variant transcript of FurinA harbouring a long 3’untranslated region (3’UTR). The alternative 3’UTR furina isoform is expressed at embryonic stages preceding organ positioning. Reporter localization and RNA-binding assays show that the furina 3’UTR forms complexes with the conserved RNA-binding protein and translational repressor Ybx1. Conditional mutant zebrafish embryos affecting ybx1 show premature and increased Furin reporter protein expression, abnormal cardiac morphogenesis and heart looping defects. Our mutant ybx1 hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and many mutant embryos show retrograde blood flow from the ventricle to the atrium. This is similar to human heart valve regurgitation patients. Our findings show an essential function for the 3’UTR element/Ybx1 regulon in translational repression of FurinA, revealing a new upstream regulatory mechanism that controls embryonic heart development, and demonstrates the ybx1 mutant as a model to study cardiac valve development and function.