CXXC5 is required for cardiac looping relating to TGFβ signaling pathway in zebrafish

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• 作者：Xiyang Peng^a ; ¹ ; Guanming Li^a ; ¹ ; Yuequn Wang^a ; ¹ ; Jian Zhuang^b ; ¹ ; Rong Luo^a ; Jimei Chen^b ; Fa Chen^a ; Yan Shi^a ; Jiani Li^b ; Zuoqiong Zhou^a ; Xiaoyang Mo^a ; Xianchu Liu^a ; Wuzhou Yuan^a ; Qun Zeng^a ; Yongqing Li^a ; Zhigang Jiang^a ; Yongqi Wan^a ; Xiangli Ye^a ; Wei Xu^a ; Xijun Wang^a ; Xiongwei Fan^a ; ^{fansha1234@aliyun.com" class="auth_mail" title="E-mail the corresponding author} ; Ping Zhu^b ; ^{tanganqier@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xiushan Wu^a ; ^{xiushanwu@yahoo.com" class="auth_mail" title="E-mail the corresponding author} ; Yun Deng^a ; ^{dengyun@hunnu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CXXC5 ; Cardiogenesis ; Tgfβ signaling pathway ; Congenital heart diseases
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：214
• 期：Complete
• 页码：246-253
• 全文大小：1199 K

文摘

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 Tgfβ 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 Tgfβ 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 Tgfβ 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 Tgfβ 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.