Dynamic regulation of estrogen receptor-α isoform expression in the mouse fallopian tube: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors

Abstract

Estrogen receptors (ERs) are members of the nuclear receptor superfamily and are involved in regulation of fallopian tube functions (i.e., enhancement of protein secretion, formation of tubal fluid, and regulation of gamete transport). However, the ER subtype-mediated mechanisms underlying these processes have not been completely clarified. Recently, we identified ERβ expression and localization in rat fallopian tubes, suggesting a potential biological function of ERβ related to calcium-dependent ciliated beating. Here we provide for the first time insight into the less studied ERα isoforms, which mediate estrogen-dependent production and secretion of IGFs in vivo. First, Western blot studies revealed that three ERα isoforms were expressed in mouse fallopian tubes. Subsequent immunohistochemical analysis showed that ERα was detected in all cell types, whereas ERβ was mainly localized in ciliated epithelial cells. Second, ERα isoform levels were dramatically downregulated in mouse fallopian tubes by treatment with E2or PPT, an ERα agonist, in a time-dependent manner. Third, the presence of ICI 182,780, an ER antagonist, blocked the E2- or PPT-induced downregulation of tubal ERα isoform expression in mice. However, alteration of ERα immunoreactivity following ICI 182,780 treatment was only detected in epithelial cells of the ampullary region. Fourth, changes in ERα isoform expression were found to be coupled to multiple E2effects on tubal growth, protein synthesis, and secretion in mouse fallopian tube tissues and fluid. In particular, E2exhibited positive regulation of IGF-I and IGF-II protein levels. Finally, using growth hormone receptor (GHR) gene-disrupted mice, we showed that regulation by E2of IGF production was independent of GH-induced GHR signaling in mouse fallopian tubes in vivo. These data, together with previous studies from our laboratory, suggest that the long-term effects of estrogen agonist promote IGF synthesis and secretion in mouse tubal epithelial cells and fallopian tube fluid via stimulation of ERα.