Rargb regulates organ laterality in a zebrafish model of right atrial isomerism.
Rargb regulates organ laterality in a zebrafish model of right atrial isomerism.
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DOI：
10.1016/j.ydbio.2012.09.001
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发表时间：
2012-12-15
影响因子：
2.7
通讯作者：
Goessling, Wolfram
中科院分区：
文献类型：
--
作者：
Garnaas, Maija K.;Cutting, Claire C.;Meyers, Alison;Kelsey, Peter B., Jr.;Harris, James M.;North, Trista E.;Goessling, Wolfram
发育信号决定胚胎发生过程中器官的形态和位置。为了发现肝脏发育的新修饰剂，我们在斑马鱼中进行了化学遗传筛选，并确定视黄酸为肝发生的正调节剂。四种RA受体的敲除表明，所有受体都会影响肝脏形成，但特定受体会产生不同的作用。Rargb敲低导致双侧肝脏，但不影响器官大小，揭示了Rargb在赋予左右位置信息方面的独特作用。在rargb morphants中可检测到肝母细胞的双侧群体，表明Rargb在肝特化过程中起作用以定位肝脏，并且原始内胚层有能力在两侧形成肝脏。心脏保持在中线和肠循环是扰动rargb变形，这表明Rargb影响侧板中胚层迁移。在体细胞发生过程中Bmp的过表达同样导致双侧肝脏和中线心脏，Bmp信号传导的抑制拯救了rargb morphant表型，表明Rargb在Bmp上游起调节器官侧性的作用。rargb的缺失导致胆管和器官偏侧性缺陷以及无脾，与人类右心房异构症的症状相似。我们的研究结果揭示了RA在调节器官偏侧性方面的新作用，并提供了一种人类异位症的动物模型。
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.
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影响因子：
11.8
作者：
Chung, Won-Suk;Shin, Chong Hyun;Stainier, Didier Y. R.
通讯作者：
Stainier, Didier Y. R.
影响因子：
--
作者：
Chen, J N;van Bebber, F;Goldstein, A M;Serluca, F C;Jackson, D;Childs, S;Serbedzija, G;Warren, K S;Mably, J D;Lindahl, P;Mayer, A;Haffter, P;Fishman, M C
通讯作者：
Fishman, M C
影响因子：
10.5
作者：
Abu-Abed, S;Dollé, P;Petkovich, M
通讯作者：
Petkovich, M
影响因子：
2.7
作者：
DERSCH, H;ZILE, MH
通讯作者：
ZILE, MH
影响因子：
56.9
作者：
Horne-Badovinac, S;Rebagliati, M;Stainier, DYR
通讯作者：
Stainier, DYR