Levi, L., Ziv, T., Admon, A., Levavi-Sivan, B., and Lubzens, E. (2012) Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish. American journal of physiology. Endocrinology and metabolism. 302(6):E626-644.
Retinal is the main retinoid stored in oviparous eggs of fish, amphibians and reptiles, reaching the oocytes in association
with vitellogenins, the yolk precursor proteins. During early pre-segmentation stages of zebrafish embryos, retinal is metabolized
to retinoic acid (RA) that regulates genes involved in cell proliferation, differentiation and tissue function, and is therefore
essential for normal embryonic development. While synthesis of vitellogenin and its regulation by 17β-estradiol (E2) were
extensively investigated, pathways for retinal synthesis remain obscure. We determined the expression pattern of 46 candidate
genes aiming at identifying enzymes associated with retinal synthesis; ascertaining whether they were regulated by E2 and
finding pathways that could fulfill the demand for retinoids during vitellogenesis.
Genes associated with retinal synthesis were up-regulated in the liver (rdh10, rdh13, sdr), and surprisingly also in the intestine
(rdh13) and ovary (rdh1, sdr), concomitantly with higher gene expression and synthesis of vitellogenins in the liver, but
also in extra-hepatic tissues, shown here for the first time. Vitellogenin synthesis in the ovary was regulated by E2. Gene
expression studies suggest that elevated retinal synthesis in the liver, intestine and ovary also depends on cleavage of carotenoids
(by Bcdo2 or Bmco1) but in the ovary it may also be contingent on higher uptake of retinol from the circulatory system (via
Stra6) and retinol synthesis from retinyl-esters (by Lpl). Decrease in oxidation (by Raldh2 or Raldh3) of retinal to retinoic
acid and/or degradation of RA (by Cyp26a1) may also facilitate higher hepatic retinal levels. Together, these processes enable
meeting the putative demands of retinal for binding to vitellogenins. Bioinformatic tools reveal multiple hormone response
elements in the studied genes, suggesting complex and intricate regulation of these processes.