Watt Alistair J, Zhao Roong, Li Jixuan, Duncan Stephen A
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53202, USA.
BMC Dev Biol. 2007 Apr 23;7:37. doi: 10.1186/1471-213X-7-37.
In the mouse, the parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm. GATA4, a zinc finger transcription factor, is strongly expressed in these endodermal domains and molecular analyses have implicated GATA4 in potentiating liver gene expression during the onset of hepatogenesis. We therefore hypothesized that GATA4 has an integral role in controlling the early stages of pancreatic and liver development.
To determine whether GATA4 contributes to development of either the pancreas or liver we characterized the formation of pancreatic and hepatic tissues in embryos derived from Gata4-/- ES cells by tetraploid embryo complementation. In the absence of GATA4, development of the liver and ventral pancreas was disrupted. At embryonic day (E) 9.5, the liver bud failed to expand although, contrary to expectations, the hepatic endoderm was able to form a pseudo-stratified epithelial liver bud that expressed hepatic genes. Moreover, as we had shown previously, the embryos lacked septum transversum mesenchyme suggesting that liver defects may be cell non-autonomous. Analyses of pancreatic development revealed a complete absence of the ventral but not the dorsal pancreas in Gata4-/- embryos. Moreover, Gata6-/- embryos displayed a similar, although less dramatic phenotype, suggesting a critical role for multiple GATA factors at the earliest stages of ventral pancreas development.
This study defines integral roles for GATA factors in controlling early development of the mammalian liver and pancreas.
在小鼠中，肝脏和腹侧胰腺的实质均由腹侧前肠内胚层的相邻区域分化而来。锌指转录因子GATA4在这些内胚层区域中强烈表达，分子分析表明GATA4在肝脏发生起始阶段增强肝脏基因表达中发挥作用。因此，我们推测GATA4在控制胰腺和肝脏发育的早期阶段具有不可或缺的作用。
为了确定GATA4是否对胰腺或肝脏的发育有贡献，我们通过四倍体胚胎互补技术，对源自Gata4-/-胚胎干细胞的胚胎中的胰腺和肝脏组织形成进行了表征。在缺乏GATA4的情况下，肝脏和腹侧胰腺的发育受到破坏。在胚胎第9.5天（E9.5），肝芽未能扩张，尽管与预期相反，肝内胚层能够形成表达肝脏基因的假复层上皮肝芽。此外，正如我们之前所表明的，胚胎缺乏横隔间质，这表明肝脏缺陷可能是非细胞自主性的。胰腺发育分析显示，Gata4-/-胚胎中完全没有腹侧胰腺，但背侧胰腺正常。此外，Gata6-/-胚胎表现出类似但不太明显的表型，这表明多种GATA因子在腹侧胰腺发育的最早阶段起关键作用。
本研究确定了GATA因子在控制哺乳动物肝脏和胰腺早期发育中的不可或缺的作用。
