Origin of Cardiac Cell Lineages Group, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, Bad Nauheim, Germany.
Dev Cell. 2012 Jul 17;23(1):58-70. doi: 10.1016/j.devcel.2012.06.005. Epub 2012 Jul 5.
Morphogenesis of the heart requires tight control of cardiac progenitor cell specification, expansion, and differentiation. Retinoic acid (RA) signaling restricts expansion of the second heart field (SHF), serving as an important morphogen in heart development. Here, we identify the LIM domain protein Ajuba as a crucial regulator of the SHF progenitor cell specification and expansion. Ajuba-deficient zebrafish embryos show an increased pool of Isl1(+) cardiac progenitors and, subsequently, dramatically increased numbers of cardiomyocytes at the arterial and venous poles. Furthermore, we show that Ajuba binds Isl1, represses its transcriptional activity, and is also required for autorepression of Isl1 expression in an RA-dependent manner. Lack of Ajuba abrogates the RA-dependent restriction of Isl1(+) cardiac cells. We conclude that Ajuba plays a central role in regulating the SHF during heart development by linking RA signaling to the function of Isl1, a key transcription factor in cardiac progenitor cells.
心脏的形态发生需要严格控制心脏祖细胞的特化、扩增和分化。视黄酸（RA）信号限制了第二心脏场（SHF）的扩增，是心脏发育中的重要形态发生素。在这里，我们确定 LIM 结构域蛋白 Ajuba 是 SHF 祖细胞特化和扩增的关键调节因子。Ajuba 缺陷的斑马鱼胚胎显示出 Isl1(+) 心脏祖细胞的增加池，随后在动脉和静脉极处的心肌细胞数量显著增加。此外，我们表明 Ajuba 结合 Isl1，抑制其转录活性，并且还需要以 RA 依赖性方式对 Isl1 表达进行自身抑制。缺乏 Ajuba 会破坏 RA 依赖性限制 Isl1(+) 心脏细胞。我们的结论是，Ajuba 通过将 RA 信号与心脏祖细胞中的关键转录因子 Isl1 的功能联系起来，在心脏发育过程中在调节 SHF 中发挥核心作用。
