Developmental regulatory system of ocular‐side‐specific asymmetric pigmentation in flounder: Critical role of retinoic acid signaling

The body color of the Pleuronectiformes is bilaterally asymmetric between right and left halves, with a dark ocular-side and a white blind-side. This body color asymmetry develops by restricted differentiation of melanophores and xanthophores on the ocular-side during metamorphosis, accompanied by migration of one eye to the future ocular-side. In this study, we elucidated the developmental regulatory system of this lateralized pigmentation. We found that in flounder, Sox10-positive chromatophore progenitors appear bilaterally both in the ocular- and blind-side skin of metamorphosing larvae, and that those arriving at the ocular-side skin differentiate into gch2-positive chromatoblasts and then chromatophores. Transient exposure of metamorphosing larvae to retinoic acid (RA)-induced progenitors on the blind-side to differentiate into gch2-positive chromatoblasts. On the contrary, exposure to an RA receptor antagonist, BMS493, suppressed the differentiation of gch2-positive chromatoblasts on the ocular-side. Thus, we demonstrated that RA is essential for flounder chromatophore progenitors to differentiate into chromatoblasts. At the time of chromatoblast differentiation on the ocular-side, cyp26b1, which inactivates RA, was upregulated on the blind-side skin compared with the ocular-side. Therefore, we surmise that ocular-side-specific pigmentation is regulated by the inhibition of RA-signaling by cyp26b1 on the blind-side.