title: The Emerging Role of FOXL2 in Regulating the Transcriptional Activation Function of Estrogen Receptor β: An Insight Into Ovarian Folliculogenesis.
abstract: Germline mutations of the fork-head transcriptional factor forkhead box L2 (FOXL2) predispose embryos to autosomal-dominant blepharophimosis-ptosis-epicanthus inversus syndrome with primary ovarian insufficiency in female patients, but the mechanisms of FOXL2 in ovarian follicular development remain elusive. Estrogens produced by ovarian granulosa cells and estrogen receptor (ER) α and ERβ play fundamental roles in ovarian pathophysiology, and a previous study revealed that ERα and ERβ physically interact with FOXL2. However, the underlying functions of these interactions have not been investigated. Herein, we report an ERβ-specific repressive function of FOXL2. Histological examination demonstrated that FOXL2 expression tends to be intense during early follicular development. Immunoprecipitation revealed that ERβ and FOXL2 interact in a ligand-independent manner. In vitro pull-down assays revealed a direct interaction between FOXL2 and the activation function (AF)-1/2 domain of ERβ. The expression of FOXL2 represses the ligand-dependent transcriptional activation of ERβ, but FOXL2 does not influence the ligand-dependent transcriptional activation of ERα. Consistent with these results, RNA interference-mediated depletion of FOXL2 stimulates the expression of the ERβ-downstream gene p450 aromatase. The convergence between FOXL2 functions and ERβ-mediated transcription in the ovary suggests the putative mechanism of FOXL2 in early-phase follicular development, which may be partially attributed to the regulation of ERβ-dependent gene expression.
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Hirano
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Houju
authors.initials: H
authors.lastname: Fu
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Akino
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Isono
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Sakurabashi
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morita
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tanikawa
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: 2 Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishi
authors.affiliation: 3 Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Harada
authors.affiliation: 4 Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Oishi
authors.affiliation: 4 Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
keywords: ERβ; FOXL2; development; follicle; ovary