Chen J N, Fishman M C
Cardiovascular Research Center, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Charlestown 02129, USA.
Development. 1996 Dec;122(12):3809-16. doi: 10.1242/dev.122.12.3809.
The fashioning of a vertebrate organ requires integration of decisions of cell fate by individual cells with those that regulate organotypic form. Logical candidates for this role, in an organ such as the heart, are genes that initiate the differentiation process leading to heart muscle and those that define the earliest embryonic heart field, but for neither class are genes defined. We cloned zebrafish Nkx2.5, a homolog of the tinman homeodomain gene needed for visceral and cardiac mesoderm formation in Drosophila. In the zebrafish, its expression is associated with cardiac precursor cells throughout development, even in the early gastrula, where the level of zebrafish Nkx2.5 is in a gradient which spatially matches the regional propensity of ventral-marginal cells to become heart. Overexpression of Nkx2.5 causes formation of disproportionally larger hearts in otherwise apparently normal embryos. Transplanted cell expressing high levels of Nkx2.5 express cardiac genes even in ectopic locales. Fibroblasts transfected with myc-tagged Nkx2.5 express cardiac genes. These effects require the homeodomain. Thus, Nkx2.5 appears to mark the earliest embryonic heart field and to be capable of initiating the cardiogenic differentiation program. Because ectopic cells or transfected fibroblasts do not beat, Nkx2.5 is likely to be but one step in the determination of cardiac myocyte cell fate. Its overexpression increases heart size, perhaps by bringing cells on the edge of the field to a threshold level for initiation of cardiac differentiation.
脊椎动物器官的形成需要单个细胞的细胞命运决定与调节器官形态的决定相互整合。在心脏等器官中，扮演这一角色的合理候选基因是那些启动导致心肌分化过程的基因以及那些定义最早胚胎心脏区域的基因，但这两类基因都尚未明确。我们克隆了斑马鱼Nkx2.5，它是果蝇中内脏和心脏中胚层形成所需的tinman同源异型域基因的同源物。在斑马鱼中，其表达在整个发育过程中都与心脏前体细胞相关，甚至在早期原肠胚中也是如此，此时斑马鱼Nkx2.5的水平呈梯度分布，在空间上与腹侧边缘细胞形成心脏的区域倾向相匹配。Nkx2.5的过表达会导致原本看似正常的胚胎中形成不成比例的更大心脏。移植表达高水平Nkx2.5的细胞即使在异位位点也会表达心脏基因。用myc标签的Nkx2.5转染的成纤维细胞会表达心脏基因。这些效应需要同源异型域。因此，Nkx2.5似乎标记了最早的胚胎心脏区域，并且能够启动心脏发生分化程序。由于异位细胞或转染的成纤维细胞不会跳动，Nkx2.5可能只是心肌细胞命运决定过程中的一个步骤。它的过表达增加了心脏大小，可能是通过将区域边缘的细胞带到启动心脏分化的阈值水平。
