Dihydrofolate reductase is required for the development of heart and outflow tract in zebrafish.
Dihydrofolate reductase is required for the development of heart and outflow tract in zebrafish.
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DOI：
10.1093/abbs/gmr098
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发表时间：
2011-12
影响因子：
3.7
通讯作者：
Shu-na Sun;Y. Gui;Qiu Jiang;Hou-yan Song
中科院分区：
文献类型：
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作者：
Shu-na Sun;Y. Gui;Qiu Jiang;Hou-yan Song
叶酸对胚胎发育非常重要，抑制叶酸可导致脊椎动物先天性心脏缺陷。二氢叶酸还原酶（DHFR）是叶酸代谢的关键酶。DHFR的功能障碍破坏了叶酸参与的关键生物过程。DHFR基因在脊椎动物进化过程中是保守的。研究DHFR在心脏发育中的作用具有重要意义。在本研究中，我们发现DHFR敲低导致斑马鱼胚胎早期发育异常。在DHFR敲低胚胎中也观察到心脏和流出道（OFT）的明显畸形。DHFR过表达挽救了DHFR敲除组中的异常表型。DHFR基因敲低对心脏发育过程中重要转录因子NKX2.5（NK 2 transcriptionfactor-related 5）、MEF 2C（myocytespecific enhancer factor 2C）、TBX 20（T-box 20）和TBX 1（T-box 1）的表达有负面影响，而DHFR基因过表达有正面影响。Hedgehog途径需要DHFR。DHFR基因敲低导致细胞增殖减少和凋亡增加，而其过表达促进细胞增殖和抑制凋亡。综上所述，我们的研究表明，DHFR通过调节基因转录和影响细胞增殖和凋亡在斑马鱼心脏和OFT的发育中起着至关重要的作用。
Folic acid is very important for embryonic development and folic acid inhibition can cause congenital heart defects in vertebrates. Dihydrofolate reductase (DHFR) is a key enzyme in folate-mediated metabolism. The dysfunction of DHFR disrupts the key biological processes which folic acid participates in. DHFR gene is conserved during vertebrate evolution. It is important to investigate the roles of DHFR in cardiac developments. In this study, we showed that DHFR knockdown resulted in the abnormal developments of zebrafish embryos in the early stages. Obvious malformations in heart and outflow tract (OFT) were also observed in DHFR knockdown embryos. DHFR overexpression rescued the abnormal phenotypes in the DHFR knockdown group. DHFR knockdown had negative impacts on the expressions of NKX2.5 (NK2 transcription factor-related 5), MEF2C (myocyte-specific enhancer factor 2C), TBX20 (T-box 20), and TBX1 (T-box 1) which are important transcriptional factors during cardiac development process, while DHFR overexpression had positive effects. DHFR was required for Hedgehog pathway. DHFR knockdown caused reduced cell proliferation and increased apoptosis, while its overexpression promoted cell proliferation and inhibited apoptosis. Taken together, our study suggested that DHFR plays crucial roles in the development of heart and OFT in zebrafish by regulating gene transcriptions and affecting cell proliferation and apoptosis.