CXXC5 is required for cardiac looping relating to TGFβ signaling pathway in zebrafish
CXXC5 is required for cardiac looping relating to TGFβ signaling pathway in zebrafish
复制标题
斑马鱼中与 TGF β 信号通路相关的心脏循环需要 CXXC5
DOI：
10.1016/j.ijcard.2016.03.201
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发表时间：
2016-07-01
影响因子：
3.5
通讯作者：
Deng, Yun
中科院分区：
文献类型：
--
作者：
Peng, Xiyang;Li, Guanming;Deng, Yun
背景：CXXC型锌指蛋白CXXC5已被报道与心血管疾病的发生有关。最近，通过对信号通路的筛选，我们发现CXXC5同时激活了转化生长因子β和心肌分化信号通路。虽然CXXC5在许多器官中的生理和病理功能已被阐明，但其在心脏中的功能仍不清楚。方法与结果：我们发现斑马鱼CXXC5与SMAD通过ZF-CXXC和MH1结构域相互作用。CXXC5在心肌细胞中的过表达增加了转化生长因子β信号通路的荧光素酶活性。Cxxc5的时空表达谱显示其在心脏发生过程中持续表达。斑马鱼cxxc5基因敲除后表现为心脏环状缺陷、心脏发育不全、心包水肿和收缩能力下降，并伴随着涉及转化生长因子β信号通路心脏环状下游基因如NKX2.5、Hand2和HAS2的下调。结论：本研究首次为cxxc5通过转化生长因子β相关信号通路调控心脏发育和心脏循环提供了体内证据。提示CXXC5可能是胎儿先天性心脏病的潜在诊断和预后指标。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Background: CXXC-type zinc-finger protein CXXC5 has been reported to be associated with the development of cardiovascular disease. Recently, through signaling pathway screening we found that CXXC5 activated Tgf beta and myocardial differentiation signaling pathways simultaneously. Although the physiological and pathological function of CXXC5 in many organs has been well elucidated, its function in heart remains unclear.Methods and results: Here, we found that zebrafish CXXC5 and SMAD were interacting through ZF-CXXC and MH1 domain. Over-expression of CXXC5 in cardiomyocyte increased the luciferase report activity of Tgf beta signaling pathway. Spatiotemporal expression profile of cxxc5 showed that it consistently expressed during cardiogenesis. Knockdown of cxxc5 in zebrafish displayed looping defects, cardiac dysplasia, pericardial edema, and decreased contraction ability, accompanied with down-regulation of members referring to cardiac looping downstream genes of Tgf beta signaling pathway, such as nkx2.5, hand2, and has2. Co-injection of hand2 mRNA with cxxc5 morpholino rescued the cardiac looping detects.Conclusion: Our study is the first to provide an in vivo evidence for cxxc5 regulating heart development and cardiac looping via Tgf beta related signaling pathway. This finding suggested that CXXC5 may serve as a possible marker that has potential diagnostic and prognostic value in fetus with congenital heart disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved.