Maternal estrogen controls retinoic acid metabolism and signaling in early vertebrate development

Fertilized eggs of lower vertebrates contain substantial amounts of steroidal hormones such as estrogen transferred from mother during oogenesis. However, molecular roles for maternal estrogen in the early embryonic development are largely unknown. Here we show that maternal estrogen and estrogen receptor-α modulate retinoic acid (RA) metabolism and RA-responsive gene expression in medaka embryos. Treatments with excess estradiol, an anti-estrogen (tamoxifen), overexpression or knockdown of estrogen receptor-α (ERα) resulted in misregulation of RA-related gene expression such as raldh2 (retinalaldehyde dehydrogenase), cyp26a1 (RA hydroxylase), fgf8 (fibroblast growth factor), rarα (RA receptor-α), and ahr1 (aryl hydrocarbon receptor). We propose that maternal estrogen/ERα plays a critical role in the feedback control of in vivo level of RA and that it also activates RA signaling for the development of hindbrain and vasculatures. This is the first report demonstrating that maternal estrogen supports successful embryonic development by controlling RA metabolism and signaling in early vertebrate embryos.Supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan

Estrogen inhibits development of yolk veins and causes blood clotting in transgenic medaka fish overexpressing estrogen receptor

We established three transgenic medaka fish lines overexpressing the medaka estrogen receptor under the constitutive medaka beta-actin promoter. The transgenic embryos became hypersensitive to estrogens (17beta-estradiol and 17alpha-ethinylestradiol), and failed to develop yolk veins while blood clots formed in the blood island within 3 days after exposure to the estrogens. The embryos developed normally if exposed to estrogen after an early neurula stage, suggesting that the sensitive stage is before neurulation. The developmental defects were recovered by incubation with an anti-estrogen, tamoxifen. These results indicate that activation of estrogen receptor caused the estrogen-induced, developmental defects. Our results show that the transgenic embryos can be used to assay the blood clotting activity of estrogenic compounds in vivo