Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
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June, 1999 ESTROGEN RECEPTOR NULL MICE 389<br />
ER� mRNA in certain regions of the rat brain, including the<br />
medial nucleus of the amygdala and the periventricular preoptic<br />
nucleus. Therefore, with preliminary studies indicating<br />
distinct tissue localization of the two ERs in the reproductive<br />
tract, the brain may be the ideal tissue for the study of<br />
possible transactivational actions of ER�/ER� heterodimers.<br />
It is important to reiterate that studies have indicated a normal<br />
expression pattern for the ER� gene in the hypothalamus<br />
of the �ERKO mouse (93, 352).<br />
Aside from the receptor-mediated genomic actions of sex<br />
steroids that have been so well characterized, the possibility<br />
of nongenomic effects of gonadal hormones and their metabolites<br />
has also received increased attention. A number of<br />
rapid responses to gonadal steroids in various tissues have<br />
been reported and are believed to occur too soon after steroid<br />
exposure to be mediated by the classical mechanism of hormone<br />
nuclear receptors; therefore, they have been termed as<br />
being “nongenomic” (reviewed in Refs. 347, 355–358). These<br />
include the rapid activation of membrane calcium channels<br />
by progesterone in the maturing oocyte and spermatozoa, by<br />
estrogens in myometrial cells, and by androgens in rat osteoblast<br />
cells (347, 355, 356). Descriptions of similar nongenomic<br />
effects of steroids in the neuroendocrine system<br />
include rapid increases in cAMP levels in neurons, modulation<br />
of the GABA-GABA A receptor function, release of<br />
GnRH and dopmamine from nerve terminals, modulation of<br />
oxytocin receptors, and the release of PRL from GH3/B6<br />
pituitary cells (343, 356, 357). Supportive experimental findings<br />
indicate the presence of membrane steroid receptors,<br />
including those for estradiol, in various cell types (359–361).<br />
Evidence that a membrane ER is structurally similar to the<br />
nuclear ER� was provided by Pappas et al. (362) in which<br />
multiple ER�-specific antibodies were shown to detect and<br />
localize ER� immunoreactivity in the cell membrane. Furthermore,<br />
Blaustein describes findings of extranuclear ER�<br />
immunoreactivity in the cytoplasm, dendritic processes, and<br />
axon terminals of neurons and suggests an active role for<br />
these receptors in neurotransmitter release (reviewed in Ref.<br />
338). Recently, Razandi et al. (363) reported the detection of<br />
membrane ER� and ER� receptors in Chinese hamster ovary<br />
(CHO) cells transfected with an expression vector of the<br />
respective receptor cDNA, indicating that the membrane and<br />
nuclear forms of each ER originate from the same transcript<br />
and exhibit similar affinities for estradiol. These studies further<br />
demonstrated that the membrane-bound ERs were G<br />
protein linked and able to elicit a variety of signal transduction<br />
events, including the induction of cell proliferation (363).<br />
In contrast, Gu et al. (364) recently employed the �ERKO<br />
mouse to illustrate that the documented rapid action of estradiol<br />
on kainate-induced currents in the hippocampus occurs<br />
in the absence of a functional ER� gene, nor does ICI-<br />
182,780 have an inhibitory effect, suggesting that ER� is not<br />
involved as well. Therefore, the putative membrane receptor<br />
involved in mediating the neuronal effect of estradiol in the<br />
hippocampus described by Gu et al. appears to be distinct<br />
from the intracellular nuclear form of the ER as well as that<br />
described by Razandi et al. (363). Regardless, the ultimate<br />
function of the nongenomic signaling pathways of the gonadal<br />
steroids in the proper organization and function of the<br />
mammalian brain remains unclear. Therefore, the ERKO mu-<br />
tant mice provide an excellent model to not only study the<br />
role of the nuclear receptors, but also further the investigations<br />
of steroid hormone actions that may be nuclear receptor<br />
independent.<br />
A comprehensive review of the neuroendocrine system is<br />
beyond the scope of this discussion and has been reviewed<br />
in detail elsewhere (337, 347). However, as was expected,<br />
distinct phenotypes in the neuroendocrine system have become<br />
evident in mice after disruption of the ER� gene. The<br />
ultimate consequences of the lack of ER� action in the neuroendocrine<br />
system are manifested in the ovary of the<br />
�ERKO female and as severe deficits in sexual and field<br />
behavior in both sexes of the �ERKO mice. Due to the relatively<br />
short time in which the �ERKO model has been<br />
available for study, no detailed characterizations of possible<br />
phenotypes in the hypothalamic-pituitary axis of this model<br />
have been carried out. Therefore, this section of the review<br />
will concentrate on what is currently known about the<br />
�ERKO, but will attempt to shed light on the possible distinct<br />
roles of both ERs based on the limited observations of the<br />
�ERKO.<br />
A. Hypothalamic-pituitary axis<br />
The hypothalamus may be thought of as the interface<br />
between the central nervous system and the endocrine system,<br />
i.e., the pituitary. The anatomical location of the hypothalamus,<br />
forming the base of the brain and residing just<br />
above the pituitary, is conducive to a function of translating<br />
neuronal signals from the brain into humoral factors that<br />
stimulate the appropriate actions in the anterior pituitary<br />
(365). The two components are connected by the hypothalamo-hypophyseal<br />
portal system, within which blood<br />
flows predominantly from the hypothalamus to the anterior<br />
pituitary, carrying the appropriate hormonal factors (365).<br />
These hormones act as releasing or inhibiting factors to control<br />
the secretory activity of the pituitary. In contrast, the<br />
posterior pituitary is connected directly to the hypothalamus<br />
via neurons passing through the pituitary stalk and functions<br />
as a storage organ for the hypothalamic hormones, oxytocin<br />
and vasopressin.<br />
The anterior pituitary is composed of at least five distinct<br />
cell types, all derived from a common primordium, which<br />
have been categorized by the particular peptide hormone<br />
they produce and secrete. These cell types are as follows,<br />
with the secretory hormone in parentheses: gonadotrophs<br />
(FSH and LH), corticotrophs (ACTH), thyrotrophs (TSH),<br />
somatotrophs (GH), and lactotrophs (PRL). Early studies<br />
employing steroid autoradiography demonstrated estrogen<br />
binding to varied degrees throughout the different cells of<br />
the anterior pituitary, although discrepancies among species<br />
are evident (reviewed in Ref. 339). These studies have been<br />
followed by those using in situ hybridization and immunohistochemistry,<br />
indicating that the majority of estradiol binding<br />
in the anterior pituitary is due to the expression of ER�<br />
(366, 367). In most species described, gonadotrophs and lactotrophs<br />
exhibit the greatest level of ER� followed by lower<br />
and varied levels of localization to the other cell types (339).<br />
Furthermore, Shupnik et al. (29, 368) have described in the rat<br />
pituitary a number of ER� mRNA isoforms characterized by