Rargb regulates organ laterality in a zebrafish model of right atrial isomerism

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.

► A chemical genetic screen identifies retinoic acid (RA) as a regulator of normal liver development. ► RA synthesis and receptor-mediated signaling are both important for hepatogenesis. ► Loss of Rargb results in organ positioning and bile duct defects as well as asplenia. ► The rargb morphant phenotype parallels the human heterotaxic syndrome right atrial isomerism, or Ivemark syndrome. ► Rargb functions upstream of BMP signaling to impact organ development.