Department of Biochemistry and Biophysics, Liver Center, Institute for Regeneration Medicine, University of California, San Francisco, CA 94158, USA.
Development. 2011 Apr;138(7):1339-48. doi: 10.1242/dev.054395.
Hepatic competence, or the ability to respond to hepatic-inducing signals, is regulated by a number of transcription factors broadly expressed in the endoderm. However, extrinsic signals might also regulate hepatic competence, as suggested by tissue explant studies. Here, we present genetic evidence that Fgf signaling regulates hepatic competence in zebrafish. We first show that the endoderm posterior to the liver-forming region retains hepatic competence: using transgenic lines that overexpress hepatic inducing signals following heat-shock, we found that at late somitogenesis stages Wnt8a, but not Bmp2b, overexpression could induce liver gene expression in pancreatic and intestinal bulb cells. These manipulations resulted in the appearance of ectopic hepatocytes in the intestinal bulb. Second, by overexpressing Wnt8a at various stages, we found that as embryos develop, the extent of the endodermal region retaining hepatic competence is gradually reduced. Most significantly, we found, using gain- and loss-of-function approaches, that Fgf10a signaling regulates this gradual reduction of the hepatic-competent domain. These data provide in vivo evidence that endodermal cells outside the liver-forming region retain hepatic competence and show that an extrinsic signal, Fgf10a, negatively regulates hepatic competence.
肝脏功能，或对肝诱导信号作出反应的能力，受广泛表达在内胚层中的许多转录因子调控。然而，组织外植体研究提示，外在信号也可能调控肝脏功能。在这里，我们提出了 Fgf 信号调控斑马鱼肝脏功能的遗传证据。我们首先表明，肝脏形成区域之后的内胚层保留了肝脏功能：通过热休克后过表达肝诱导信号的转基因系，我们发现，在晚期体节形成阶段，Wnt8a，但不是 Bmp2b，过表达可在胰腺和肠球细胞中诱导肝脏基因表达。这些操作导致肠球中出现异位肝细胞。其次，通过在不同阶段过表达 Wnt8a，我们发现随着胚胎发育，保留肝脏功能的内胚层区域的范围逐渐缩小。最重要的是，我们通过获得和丧失功能的方法发现，Fgf10a 信号调控了肝脏功能域的这种逐渐缩小。这些数据提供了体内证据表明，肝脏形成区域之外的内胚层细胞保留了肝脏功能，并表明外在信号 Fgf10a 负调控肝脏功能。
