Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Hepatology. 2010 Mar;51(3):1037-45. doi: 10.1002/hep.23387.
During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost.
Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. These results suggest that a common molecular mechanism may underlie liver and pectoral fin specification during piscine embryogenesis.
在脊椎动物胚胎发生过程中，肝脏沿着内胚层原始肠道管的精确位置发育，这是由于相邻中胚层组织传递的信号所致。尽管已经有几种信号分子与肝脏形成有关，但调节肝脏特化的分子机制仍不清楚。我们之前在斑马鱼中进行了筛选，以分离出肝脏发育受损的突变体。斑马鱼 hio 突变体表现出明显的（但短暂的）肝脏特化缺陷，类似于在斑马鱼 prometheus（prt）突变体中发现的肝脏形成缺陷，prt 突变发生在 wnt2bb 基因中。除了肝脏异常外，hio 突变体还缺乏胸鳍，并且在孵化后死亡。定位克隆表明，hio 突变影响编码视黄醛脱氢酶 2（RALDH2）的 raldh2 基因，RALDH2 是负责视黄酸（RA）生物合成的主要酶。斑马鱼中 raldh2 的突变排除了胸鳍的发育。有趣的是，在 hio 突变体中，与肝脏形成内胚层直接相邻的侧板中胚层（LPM）中 wnt2bb 的表达完全丢失。
我们的数据揭示了一个意想不到的发现，即 RA 信号正向调节 wnt2bb 基因表达，这是在斑马鱼中肝脏特化所必需的。这些结果表明，在鱼类胚胎发生过程中，肝脏和胸鳍特化可能存在共同的分子机制。
