Estrogen action in the estrogen receptor α-knockout mouse: is this due to ER-β?

Abstract

In vivo autoradiographic studies have shown that neurons in the estrogen receptor-␣ knockout (ERKO) mouse brain are capable of concentrating radiolabeled estrogen. In one region of the ERKO hypothalamus that binds estrogen, the preoptic area, we have also shown that a variety of estrogenic compounds modulate the expression of progesterone receptor. Recently, a second estrogen receptor (ER-␤) was isolated from the rat prostate. In situ hybridization studies have demonstrated that ER-␤ mRNA is present in the rat brain as well as the preoptic area of the ERKO mouse brain. Interestingly, ER-␤ mRNA was also detected in regions of the brain where the classical ER is sparse or absent, including the cerebral cortex and hippocampus. Together, the results of these studies suggest the presence and functionality of a nonclassical estrogen receptor in the ERKO brain and provided evidence that this receptor may be ER-␤. Moreover, the localization of ER-␤ mRNA in many new brain regions, including those associated with learning and memory, may provide new insight about the anatomical substrate for estrogen action in the brain.Keywords: ERKO; rat; steroid; cortex; hippocampus Estrogen has a profound effect on the developing and adult mammalian brain. In the developing brain, estrogen action has been shown to promote neuronal differentiation and is thought to establish a sex dimorphism in the 'wiring' of certain neuronal pathways. The differential action of estrogen on the brain determines the phenotype of adult brain function, including the pattern of gonadotropin release, proceptive and receptive behavior and other aspects of procreation. It is generally accepted that estrogen regulates these physiological events by binding to its nuclear estrogen receptor (ER), interacting with a specific DNA response element and thereby modulating the expression of certain genes. Through the use of a variety of histochemical techniques, 1-4 ER has been detected in anatomically distinct regions of the brain, areas where estrogen has been shown to modulate events essential for procreation. Studies with a transgenic mouse which lacks a functional ER have verified the importance of ER in procreation, since ER knockout (ERKO) mice are infertile, probably due to deficits in reproductive behavior and an abnormal estrous cycle. 5 observations), suggested that some genes that are regulated by estrogen in the wild-type animal were still sensitive to changes in estrogen in the ERKO mouse brain.In order to characterize the residual estrogen activity seen in the ERKO mouse brain, we used high resolution steroid autoradiography 6 with an iodinated estrogen ( 125 I-estrogen) to assess the presence and distribution of estrogen-binding sites. This technique was selected because it allowed us to detect any estrogenbinding site, including ER, splicing variants of ER or unknown estrogen receptors, while techniques such as in situ hybridization and immunocytochemistry were limited to evaluating known mRNAs or proteins. In these studies, ERKO and wild-type mice w...

Circadian parameters are altered in two strains of mice with transgenic modifications of estrogen receptor subtype 1

“…In humans, there are estrogen receptors (ESR1 and ESR2) in the SCN, with significantly greater ESR1 expression in females relative to males (Kruijver & Swaab ). The distribution of estrogen receptors in the mouse brain is less clear, although there is evidence for both ESR1 and ESR2 in the SCN with ESR2 being relatively more abundant (Shughrue , Mitra et al . , Vida et al .…”

Differential expression of estrogen receptor alpha and beta in rat dorsal root ganglion neurons

“…More recently, immunocytochemistry (Cintra et al, 1986;DonCarlos et al, 1991;Koch and Ehret, 1989;Warembourg et al, 1989) and in situ hybridization techniques (DonCarlos, 1996;Shughrue et al, 1992;Simerly et al, 1990) have been used to detect estrogen receptors and their encoding mRNAs in the nervous system. Recently, the Shughrue laboratory used a gene knockout mouse in which the known ER␣ gene was disrupted (Lubahn et al, 1993) and found that 125 I-estrogen binding still occurred in some regions of the CNS (Shughrue, 1998;Shughrue et al, 1997b). This clearly suggested that another estrogen binding protein, besides the classical ''uterine'' form of ER, was present in the CNS of these gene knockout mice.…”

Differential expression of estrogen receptor alpha and beta in rat dorsal root ganglion neurons

“…More recently, immunocytochemistry (Cintra et al, 1986;Don-Carlos et al, 1991;Koch and Ehret, 1989;Warembourg et al, 1989) and in situ hybridization techniques (Don-Carlos, 1996;Shughrue et al, 1992;Simerly et al, 1990) have been used to detect estrogen receptors and their encoding mRNAs in the nervous system. Recently, the Shughrue laboratory used a gene knockout mouse in which the known ER␣ gene was disrupted (Lubahn et al, 1993) and found that 125 I-estrogen binding still occurred in some regions of the CNS (Shughrue, 1998;Shughrue et al, 1997b). This clearly suggested that another estrogen binding protein, besides the classical ''uterine'' form of ER, was present in the CNS of these gene knockout mice.…”

“…Recent studies have demonstrated a differential distribution of ER␤ and ER␣ mRNA in several brain regions (Shughrue, 1998;Shughrue et al, 1996Shughrue et al, , 1997a. While some CNS regions appear to contain both ER␣ and ER␤ mRNAs, other regions contain only one or the other mRNA.…”