MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
Development. 2011 Aug;138(16):3557-68. doi: 10.1242/dev.055921. Epub 2011 Jul 19.
The vertebrate liver, pancreas and lung arise in close proximity from the multipotent foregut endoderm. Tissue-explant experiments uncovered instructive signals emanating from the neighbouring lateral plate mesoderm, directing the endoderm towards specific organ fates. This suggested that an intricate network of signals is required to control the specification and differentiation of each organ. Here, we show that sequential functions of Wnt2bb and Wnt2 control liver specification and proliferation in zebrafish. Their combined specific activities are essential for liver specification, as their loss of function causes liver agenesis. Conversely, excess wnt2bb or wnt2 induces ectopic liver tissue at the expense of pancreatic and anterior intestinal tissues, revealing the competence of intestinal endoderm to respond to hepatogenic signals. Epistasis experiments revealed that the receptor frizzled homolog 5 (fzd5) mediates part of the broader hepatic competence of the alimentary canal. fzd5 is required for early liver formation and interacts genetically with wnt2 as well as wnt2bb. In addition, lack of both ligands causes agenesis of the swim bladder, the structural homolog of the mammalian lung. Thus, tightly regulated spatiotemporal expression of wnt2bb, wnt2 and fzd5 is central to coordinating early liver, pancreas and swim bladder development from a multipotent foregut endoderm.
脊椎动物的肝脏、胰腺和肺起源于多能前肠内胚层，彼此相邻。组织培养实验揭示了来自邻近侧板中胚层的指导信号，将内胚层引导至特定的器官命运。这表明需要一个复杂的信号网络来控制每个器官的特化和分化。在这里，我们表明 Wnt2bb 和 Wnt2 的顺序功能控制着斑马鱼肝脏的特化和增殖。它们的共同特定活性对于肝脏的特化是必不可少的，因为它们的功能丧失会导致肝脏发育不全。相反，过多的 wnt2bb 或 wnt2 以牺牲胰腺和前肠组织为代价诱导异位肝组织，揭示了肠内胚层对肝发生信号的反应能力。上位性实验表明，受体 frizzled 同源物 5（fzd5）介导了肠道对肝脏更广泛的特化能力的一部分。fzd5 对于早期肝脏形成是必需的，并且与 wnt2 以及 wnt2bb 在遗传上相互作用。此外，两种配体的缺失都会导致鳔的发育不全，鳔是哺乳动物肺的结构同源物。因此，wnt2bb、wnt2 和 fzd5 的紧密调控时空表达对于协调多能前肠内胚层中早期肝脏、胰腺和鳔的发育是至关重要的。
