Ober Elke A, Olofsson Birgitta, Mäkinen Taija, Jin Suk-Won, Shoji Wataru, Koh Gou Young, Alitalo Kari, Stainier Didier Y R
Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, University of California, San Francisco, California 94143-0448, USA.
EMBO Rep. 2004 Jan;5(1):78-84. doi: 10.1038/sj.embor.7400047.
During embryogenesis, complex morphogenetic events lead endodermal cells to coalesce at the midline and form the primitive gut tube and associated organs. While several genes have recently been implicated in endoderm differentiation, we know little about the genes that regulate endodermal morphogenesis. Here, we show that vascular endothelial growth factor C (Vegfc), an angiogenic as well as a lymphangiogenic factor, is unexpectedly involved in this process in zebrafish. Reducing Vegfc levels using morpholino antisense oligonucleotides, or through overexpression of a soluble form of the VEGFC receptor, VEGFR-3, affects the coalescence of endodermal cells in the anterior midline, leading to the formation of a forked gut tube and the duplication of the liver and pancreatic buds. Further analyses indicate that Vegfc is additionally required for the initial formation of the dorsal endoderm. We also demonstrate that Vegfc is required for vasculogenesis as well as angiogenesis in the zebrafish embryo. These data argue for a requirement of Vegfc in the developing vasculature and, more surprisingly, implicate Vegfc signalling in two distinct steps during endoderm development, first during the initial differentiation of the dorsal endoderm, and second in the coalescence of the anterior endoderm to the midline.
在胚胎发生过程中，复杂的形态发生事件导致内胚层细胞在中线处合并，形成原始肠管及相关器官。尽管最近有几个基因与内胚层分化有关，但我们对调节内胚层形态发生的基因了解甚少。在此，我们表明血管内皮生长因子C（Vegfc），一种血管生成和淋巴管生成因子，在斑马鱼的这一过程中意外地发挥了作用。使用吗啉代反义寡核苷酸降低Vegfc水平，或通过过表达VEGFC受体VEGFR-3的可溶性形式，会影响前中线内胚层细胞的合并，导致形成叉状肠管以及肝脏和胰腺芽的重复。进一步分析表明，Vegfc也是背侧内胚层初始形成所必需的。我们还证明，Vegfc在斑马鱼胚胎的血管发生和血管生成中也是必需的。这些数据表明在发育中的脉管系统中需要Vegfc，更令人惊讶的是，Vegfc信号在内胚层发育的两个不同阶段发挥作用，首先是在背侧内胚层的初始分化过程中，其次是在前侧内胚层向中线的合并过程中。
