Niu Zhiyv, Iyer Dinakar, Conway Simon J, Martin James F, Ivey Kathryn, Srivastava Deepak, Nordheim Alfred, Schwartz Robert J
Center for Cardiovascular Development, Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17824-9. doi: 10.1073/pnas.0805491105. Epub 2008 Nov 12.
Our conditional serum response factor (SRF) knockout, Srf (Cko), in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand1 and Smyd1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the Srf(CKO) mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRF point mutants that block cofactor interactions. In the absence of SRF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.
我们在心脏形成区域条件性敲除血清反应因子（SRF），即Srf（Cko），阻断了节律性跳动心肌细胞的出现，这是由心脏富集转录因子缺失导致的最早心脏缺陷之一。转录和染色质重塑因子Hand1和Smyd1、肌原纤维蛋白Acta1、Acta2、Myl3和Myom1以及通道蛋白钙激活钾通道基因活性（KCNMB1）在Srf（CKO）突变心脏中的表达均显著减弱。通过用阻断辅因子相互作用的SRF点突变体对SRF缺失的胚胎干细胞进行病毒拯救，证明了组合辅因子与SRF相互作用作为调节有组织肌节出现的主要决定因素的必要作用。在缺乏与生物矿化相关的SRF基因的情况下，GATA-6、骨形态发生蛋白4（BMP4）和骨膜蛋白强烈上调，同时许多SRF依赖性微小RNA（包括miR1）下调，miR1对GATA-6的诱导具有强大的沉默活性，导致BMP4和骨膜蛋白下调。
