Program in Development and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
Development. 2011 Aug;138(15):3113-23. doi: 10.1242/dev.064279. Epub 2011 Jun 29.
Development of the heart requires recruitment of cardiovascular progenitor cells (CPCs) to the future heart-forming region. CPCs are the building blocks of the heart, and have the potential to form all the major cardiac lineages. However, little is known regarding what regulates CPC fate and behavior. Activity of GATA4, SMARCD3 and TBX5 - the `cardiac BAF' (cBAF) complex, can promote myocardial differentiation in embryonic mouse mesoderm. Here, we exploit the advantages of the zebrafish embryo to gain mechanistic understanding of cBAF activity. Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. In transplantation experiments, cBAF acts cell autonomously to promote cardiac fate. Remarkably, cells overexpressing cBAF migrate to the developing heart and differentiate as cardiomyocytes, endocardium and smooth muscle. This is observed even in host embryos that lack endoderm or cardiac mesoderm. Our results reveal an evolutionarily conserved role for cBAF activity in cardiac differentiation. Importantly, they demonstrate that Smarcd3b and Gata5 can induce a primitive, CPC-like state.
心脏的发育需要将心血管祖细胞（CPCs）募集到未来的心脏形成区域。CPCs 是心脏的构建块，具有形成所有主要心脏谱系的潜力。然而，关于调节 CPC 命运和行为的因素知之甚少。GATA4、SMARCD3 和 TBX5 的活性——“心脏 BAF”（cBAF）复合物，可以促进胚胎鼠中胚层的心肌分化。在这里，我们利用斑马鱼胚胎的优势来获得对 cBAF 活性的机制理解。斑马鱼中 smarcd3b 和 gata5 的过表达会导致心脏增大，而 cBAF 成分的组合缺失会抑制心脏分化。在移植实验中，cBAF 以细胞自主的方式发挥作用，促进心脏命运。值得注意的是，过表达 cBAF 的细胞迁移到正在发育的心脏，并分化为心肌细胞、心内膜和平滑肌。即使在缺乏内胚层或心脏中胚层的宿主胚胎中也观察到这种情况。我们的研究结果揭示了 cBAF 活性在心脏分化中的保守作用。重要的是，它们表明 Smarcd3b 和 Gata5 可以诱导原始的 CPC 样状态。
