Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function
Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function
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DOI：
10.1371/journal.pone.0212992
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发表时间：
2019-03-06
期刊：
影响因子：
3.7
通讯作者：
Mohun, Timothy
中科院分区：
文献类型：
--
作者：
Dupays, Laurent;Towers, Norma;Mohun, Timothy
已知同源域转录因子NKX 2 -5对于正常心脏发育和心脏功能都是必需的。但其下游效应子的身份及其在心脏祖细胞分化过程中的功能尚不清楚。我们已经使用转基因分析和CRISPR介导的消融来鉴定弗林蛋白酶基因的心脏增强子。弗林蛋白酶基因，编码前蛋白转化酶，直接抑制NKX 2 -5。CPCs中弗林蛋白酶的缺失是胚胎致死的，突变的心脏在流出道中显示出一系列异常。这些缺陷与CPC的增殖减少和过早分化有关。在分化的心肌细胞中缺失弗林蛋白酶导致存活的成年突变小鼠显示PR间期延长，这是与Nkx 2 -5的小鼠和人突变体的表型一致的表型。我们的研究结果表明，弗林蛋白酶介导心脏中Nkx 2 -5功能的某些方面。
The homeodomain transcription factor NKX2-5 is known to be essential for both normal heart development and for heart function. But little is yet known about the identities of its downstream effectors or their function during differentiation of cardiac progenitor cells (CPCs). We have used transgenic analysis and CRISPR-mediated ablation to identify a cardiac enhancer of the Furin gene. The Furin gene, encoding a proprotein convertase, is directly repressed by NKX2-5. Deletion of Furin in CPCs is embryonic lethal, with mutant hearts showing a range of abnormalities in the outflow tract. Those defects are associated with a reduction in proliferation and premature differentiation of the CPCs. Deletion of Furin in differentiated cardiomyocytes results in viable adult mutant mice showing an elongation of the PR interval, a phenotype that is consistent with the phenotype of mice and human mutant for Nkx2-5. Our results show that Furin mediate some aspects of Nkx2-5 function in the heart.