The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis
The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis
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DOI：
10.1242/dev.050526
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发表时间：
2010-06-01
期刊：
影响因子：
4.6
通讯作者：
Burns, Caroline E.
中科院分区：
文献类型：
--
作者：
Deacon, Dekker C.;Nevis, Kathleen R.;Burns, Caroline E.
发现驱动心脏形态发生的遗传和细胞机制仍然是一个基本目标，因为三维结构极大地影响了功能能力。在发育过程中，以心肌细胞大小和形状的局部变化为特征的原始管形成精确轮廓的腔室。这些局部变化是如何实现的仍然难以捉摸。在这里，我们在斑马鱼中表明，通过直接抑制内收蛋白3 (add3), microRNA-143 （miR-143）是室形态形成所必需的，内收蛋白3编码f -肌动蛋白封盖蛋白。miR-143的敲低或miR-143-add3相互作用的破坏抑制心室心肌细胞f -肌动蛋白重塑，从而阻断其正常生长和伸长，导致心室塌陷和收缩力下降。通过马赛克分析，我们发现miR-143和add3细胞自主作用，控制f -肌动蛋白动力学和细胞形态。由于适当的腔室出现依赖于细胞骨架聚合的精确控制，Add3代表了一个有吸引力的靶标，可以通过均匀的信号（如miR-143）和未发现的局部信号进行微调。总之，我们的数据揭示了miR-143-add3遗传途径通过主动调节心肌细胞形态对心室形成和功能至关重要。
Discovering the genetic and cellular mechanisms that drive cardiac morphogenesis remains a fundamental goal, as three-dimensional architecture greatly impacts functional capacity. During development, accurately contoured chambers balloon from a primitive tube in a process characterized by regional changes in myocardial cell size and shape. How these localized changes are achieved remains elusive. Here, we show in zebrafish that microRNA-143 (miR-143) is required for chamber morphogenesis through direct repression of adducin3 (add3), which encodes an F-actin capping protein. Knockdown of miR-143 or disruption of the miR-143-add3 interaction inhibits ventricular cardiomyocyte F-actin remodeling, which blocks their normal growth and elongation and leads to ventricular collapse and decreased contractility. Using mosaic analyses, we find that miR-143 and add3 act cell-autonomously to control F-actin dynamics and cell morphology. As proper chamber emergence relies on precise control of cytoskeletal polymerization, Add3 represents an attractive target to be fine-tuned by both uniform signals, such as miR-143, and undiscovered localized signals. Together, our data uncover the miR-143-add3 genetic pathway as essential for cardiac chamber formation and function through active adjustment of myocardial cell morphology.