Characterization of evolutionary trend in squamate estrogen receptor sensitivity

Ryohei Yatsu, Yoshinao Katsu, Satomi Kohno, Takeshi Mizutani, Yukiko Ogino, Yasuhiko Ohta, Jan Myburgh, Johannes H. van Wyk, Louis J. Guillette, Shinichi Miyagawa, Taisen Iguchi

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Steroid hormones are a key regulator of reproductive biology in vertebrates, and are largely regulated via nuclear receptor families. Estrogen signaling is regulated by two estrogen receptor (ER) subtypes alpha and beta in the nucleus. In order to understand the role of estrogen in vertebrates, these ER from various species have been isolated and were functionally analyzed using luciferase reporter gene assays. Interestingly, species difference in estrogen sensitivity has been noted in the past, and it was reported that snake ER displayed highest estrogen sensitivity. Here, we isolated additional ER from three lizards: chameleon (Bradypodion pumilum), skink (Plestiodon finitimus), and gecko (Gekko japonicus). We have performed functional characterization of these ERs using reporter gene assay system, and found high estrogen sensitivity in all three species. Furthermore, comparison with results from other tetrapod ER revealed a seemingly uniform gradual pattern of ligand sensitivity evolution. In silico 3D homology modeling of the ligand-binding domain revealed structural variation at three sites, helix 2, and juncture between helices 8 and 9, and caudal region of helix 10/11. Docking simulations indicated that predicted ligand-receptor interaction also correlated with the reporter assay results, and overall squamates displayed highest stabilized interactions. The assay system and homology modeling system provides tool for in-depth comparative analysis of estrogen function, and provides insight toward the evolution of ER among vertebrates.

Original languageEnglish
Pages (from-to)88-95
Number of pages8
JournalGeneral and Comparative Endocrinology
Publication statusPublished - 1 Nov 2016



  • Estrogen receptor
  • Estrogen sensitivity
  • Evolution of estrogen receptor
  • Squamates

Cite this

Yatsu, R., Katsu, Y., Kohno, S., Mizutani, T., Ogino, Y., Ohta, Y., Myburgh, J., van Wyk, J. H., Guillette, L. J., Miyagawa, S., & Iguchi, T. (2016). Characterization of evolutionary trend in squamate estrogen receptor sensitivity. General and Comparative Endocrinology, 238, 88-95.