Humans and other terrestrial vertebrates contain two estrogen receptors (ERs), ER-alpha and ER-beta. Among cartilaginous fish (sharks, rays, skates), which are jawless vertebrates that evolved about 525 million years ago, only activation by steroids of ER-beta orthologs has been character-ized. To remedy this gap in understanding estrogen signaling in jawless vertebrates, we studied estrogen activation of orthologs of human ER-alpha and ER-beta. Unexpectedly, we found that C. milii contained three estrogen-responsive ER-alpha genes: ER-alpha1 (596 amino acids), ER-alpha-2 (600 amino acids), and ER-alpha-3 (599 amino acids) with strong sequence similarity to each other. We also found an estrogen-unresponsive gene, ER-alpha4 (561 amino acids), with a 39 amino acid deletion in the DNA-binding domain. An estrogen-responsive ER-beta ortholog (580 amino acids) also was present in C. milii. The three active C. milii ER-alphas have a similar length to human ER-alpha (595 amino acids); however, C. milii ER-beta is longer than human ER-beta (530 amino acids). We determined the half-maximal response (EC50) and fold-activation to estradiol (E2), estrone (E1), and estriol (E3) of C. milii ER-alpha1, ER-alpha2, ER-alpha3, and ER-beta. Among these estrogens, E2 had the lowest EC50 for all four ERs. Fold-activation by E2 and E3 was similar for ER-alpha1, ER-alpha2, ER-alpha3, and ER-beta. Overall, estrogen activation of C. milii ER-alpha and ER-beta was similar to that for human ER-alpha and ER-beta indicating substantial conservation of the vertebrate ER in the 525 million years since the diver-gence of cartilaginous fish and humans from a common ancestor.
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