MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development.
MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development.
复制标题
DOI：
10.1371/journal.pone.0050536
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pitto L
中科院分区：
文献类型：
--
作者：
Chiavacci E;Dolfi L;Verduci L;Meghini F;Gestri G;Evangelista AM;Wilson SW;Cremisi F;Pitto L
tbx 5是T-box基因家族的成员之一，编码介导脊椎动物心脏发育的关键转录因子之一。Tbx 5在心脏发育中的功能似乎对基因剂量非常敏感，因为单倍不足和基因复制都会产生与Holt−Oram综合征（HOS）相关的心脏异常，HOS是一种高度外显的常染色体显性疾病，其特征是不同严重程度的先天性心脏缺陷和上肢畸形。这表明，紧密整合的microRNA和转录因子的心脏遗传电路提供了一个丰富和强大的阵列的监管相互作用，以控制心脏基因的表达。基于这些考虑，我们进行了计算机筛选，以鉴定嵌入对Tbx 5剂量高度敏感的基因中的microRNA。在鉴定的microRNA中，我们将注意力集中在miR-218-1上，它与其宿主基因slit 2一起参与心脏发育。我们发现tbx 5和miR-218在小鼠P19 CL 6细胞心肌细胞分化过程中的相关表达。在斑马鱼胚胎中，我们发现Tbx 5和miR-218失调对心脏发育有严重影响，影响早期心脏形态发生。有趣的是，下调miR-218能够挽救由tbx 5过表达产生的心脏缺陷，支持miR-218是心脏发育中Tbx 5的关键介导物的观点，并表明其可能参与心脏畸形的发生。
tbx5, a member of the T-box gene family, encodes one of the key transcription factors mediating vertebrate heart development. Tbx5 function in heart development appears to be exquisitely sensitive to gene dosage, since both haploinsufficiency and gene duplication generate the cardiac abnormalities associated with Holt−Oram syndrome (HOS), a highly penetrant autosomal dominant disease characterized by congenital heart defects of varying severity and upper limb malformation. It is suggested that tight integration of microRNAs and transcription factors into the cardiac genetic circuitry provides a rich and robust array of regulatory interactions to control cardiac gene expression. Based on these considerations, we performed an in silico screening to identify microRNAs embedded in genes highly sensitive to Tbx5 dosage. Among the identified microRNAs, we focused our attention on miR-218-1 that, together with its host gene, slit2, is involved in heart development. We found correlated expression of tbx5 and miR-218 during cardiomyocyte differentiation of mouse P19CL6 cells. In zebrafish embryos, we show that both Tbx5 and miR-218 dysregulation have a severe impact on heart development, affecting early heart morphogenesis. Interestingly, down-regulation of miR-218 is able to rescue the heart defects generated by tbx5 over-expression supporting the notion that miR-218 is a crucial mediator of Tbx5 in heart development and suggesting its possible involvement in the onset of heart malformations.
登录
查看更多内容
影响因子：
1.2
作者：
Albalat, Ricard;Baquero, Mireia;Minguillon, Carolina
通讯作者：
Minguillon, Carolina
影响因子：
4.6
作者：
Fish, Jason E.;Wythe, Joshua D.;Woo, Stephanie
通讯作者：
Woo, Stephanie
影响因子：
4.6
作者：
Goetz, Sarah C.;Brown, Daniel D.;Conlon, Frank L.
通讯作者：
Conlon, Frank L.
影响因子：
11.2
作者：
Alajez, Nehad M.;Lenarduzzi, Michelle;Liu, Fei-Fei
通讯作者：
Liu, Fei-Fei
影响因子：
4.6
作者：
Hatcher, CJ;Diman, NYSG;Basson, CT
通讯作者：
Basson, CT