Comprehensive elucidation of developmental functions of arachidonic acid-derived lipid mediators in zebrafish.

Abstract

Prostaglandins (PGs) and leukotrienes (LTs) are major physiologically active lipid, which are biosynthesized from arachidonic acid (AA). AA is released from membrane phospholipids by phospholipase A2 (PLA2), and thus PGs and LTs are derived from membrane phospholipids. Zebrafish is a vertebrate model organism that has been widely used in the studies on development and drug discovery for the reasons as follows: (i) embryo development occurs outside the maternal body, (ii) embryo is transparent, (iii) high conservation between human and zebrafish genes, etc. Nevertheless, the systematic identification and characterization of zebrafish PG and LT receptors have not been performed. Therefore, we identified twelve zebrafish PG receptors and characterized their pharmacological properties. Furthermore, to identify the physiological role of zebrafish PG receptors, we generated each receptor-deficient zebrafish, and analyzed developmental processes. Here, we report that PGE2 plays essential roles in the embryonic lymphatic development through the EP3 receptor, one of the PGE2 receptors. Using pharmacological and genetic approaches, we demonstrated that the COX1-derived PGE2-EP3 pathway is required for embryonic lymphatic development by upregulating the expression of critical factors for the lymphatic specification. We recently focused the zebrafish cysteinyl LT (cysLT) receptors, cloned four zebrafish cysLT receptors, and analyzed the expression profile of these receptors in developmental stages. As results, we revealed that the four zebrafish cysLT receptors show unique tissue distribution patterns. Each receptor may hence be involved in unique physiological functions. This work provides further insights into the diverse functions of arachidonate metabolites in zebrafish.