Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Dev Biol. 2012 Dec 15;372(2):178-89. doi: 10.1016/j.ydbio.2012.09.001. Epub 2012 Sep 13.
Developmental signals determine organ morphology and position during embryogenesis. To discover novel modifiers of liver development, we performed a chemical genetic screen in zebrafish and identified retinoic acid as a positive regulator of hepatogenesis. Knockdown of the four RA receptors revealed that all receptors affect liver formation, however specific receptors exert differential effects. Rargb knockdown results in bilateral livers but does not impact organ size, revealing a unique role for Rargb in conferring left-right positional information. Bilateral populations of hepatoblasts are detectable in rargb morphants, indicating Rargb acts during hepatic specification to position the liver, and primitive endoderm is competent to form liver on both sides. Hearts remain at the midline and gut looping is perturbed in rargb morphants, suggesting Rargb affects lateral plate mesoderm migration. Overexpression of Bmp during somitogenesis similarly results in bilateral livers and midline hearts, and inhibition of Bmp signaling rescues the rargb morphant phenotype, indicating Rargb functions upstream of Bmp to regulate organ sidedness. Loss of rargb causes biliary and organ laterality defects as well as asplenia, paralleling symptoms of the human condition right atrial isomerism. Our findings uncover a novel role for RA in regulating organ laterality and provide an animal model of one form of human heterotaxia.
发育信号在胚胎发生过程中决定器官的形态和位置。为了发现新的肝脏发育调节剂，我们在斑马鱼中进行了化学遗传学筛选，并鉴定出视黄酸是肝发生的正调节剂。四种 RA 受体的敲低表明所有受体都影响肝脏形成，但特定受体产生不同的影响。Rargb 的敲低导致双侧肝脏，但不影响器官大小，这表明 Rargb 在赋予左右位置信息方面具有独特的作用。在 rargb 突变体中可以检测到双侧的肝母细胞群体，表明 Rargb 在肝脏特化过程中发挥作用，将肝脏定位，并使原始内胚层有能力在两侧形成肝脏。心脏仍然位于中线，肠道环化在 rargb 突变体中受到干扰，表明 Rargb 影响侧板中胚层的迁移。在体节形成过程中过度表达 Bmp 同样导致双侧肝脏和中线心脏，并且抑制 Bmp 信号通路可以挽救 rargb 突变体的表型，这表明 Rargb 在上游作用于 Bmp 来调节器官的偏侧性。Rargb 的缺失导致胆管和器官偏侧性缺陷以及脾缺失，与人类右心房异构症的症状相似。我们的发现揭示了 RA 在调节器官偏侧性中的新作用，并提供了一种人类异位发生的动物模型。
