Epidermal Growth Factor Activates Reproductive Behavior Independent of Ovarian Steroids in Female Rodents

Abstract

Sex steroids exert profound influence on neural development and function through activation of intranuclear receptors. However, during sexual differentiation and at onset of puberty, intracerebral estrogen (E) availability is subsequent to these effects. The potent mitogen epidermal growth factor (EGF) activates estrogen receptor (ER)-dependent transcription in cultured cells in the absence of exogenous E. Since reproductive behavior in female rodents is the result of E-dependent transcriptional activity and protein synthesis, lordosis serves as a well established in vivo model for probing cellular and molecular mechanisms of steroid receptor-dependent behavior. Here we demonstrate that EGF can signal through the classical E receptor (ERalpha) to alter in vivo function in rodent central nervous system. EGF and EGF receptor ligands induced lordosis in a dose- and time-dependent manner in the absence of steroid treatment in ovariectomized rats and mice. Using antisense oligonucleotides, pharmacological and antibody blockade, and mutant mice, we also report that this behavioral responsiveness is mediated through ERalpha by specific stimulation of membrane-bound EGF receptors and EGF receptor-specific tyrosine kinase rather than by direct ligand activation of the ERalpha. Of biological significance, delayed onset of puberty and the absence of synchronization between reproductive behavior and ovulation was detected in intact mutant Wa-2 mice that express a naturally occurring point mutation in the EGF receptor. To our surprise, EGF-mediated behavior was independent of progesterone (P) and progesterone receptor (PR) since antiprogestins, PR antisense oligonucleotides, and targeted disruption of PR in ovariectomized transgenic mice failed to impede the display of lordosis after EGF. Finally, we also found that another growth factor, insulin-like growth factor-1, which provokes ER-dependent transcription in vitro, activates mating behavior in a similar E-independent manner. Thus, growth factor mediation of ER-targeted function may be a universal feature in the rodent central nervous system, raising critical questions about the role of growth factors in mediating ER-dependent processes in development and reproduction.

Estrogen receptor ß is involved in the anorectic action of estrogen

“…A large number of studies 28 successfully investigated the neuroendocrine and behavioral effects of intracerebral administration of antisense ODN including antisense ODN for ER-a. 29,30 In the present study, specific effects of the antisense ODN for ER-ß were confirmed using two different sequences of antisense ODN and control sense and scrambled ODN. This was further supported by the results of immunoblotting.…”

“…experiments. 29,30 The finding in ER-a knockout mice provides some information on this point. In ER-a knockout mice, energy expenditure was significantly reduced compared to that in wild-type mice, whereas energy intake was unchanged, 11 suggesting that ER-a is not indispensable for the anorectic action of estrogen but is critical to energy expenditure.…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…The importance of growth factors for female sexual behavior is further illustrated by observations that epidermal growth factor (EGF) and also IGF-I can, in the absence of estrogen and progesterone (within 1-4 h of i.c.v. administration), induce mating behavior in rats and mice, in part, through an ERα-dependent mechanism (Apostolakis et al, 2000). This relatively rapid, ligand-independent ER action is in striking contrast to the well established finding that estrogen priming over a period of at least 24 h is needed for progesterone induction of female reproductive behavior .…”

ERβ-Selective Estrogen Receptor Modulators Produce Antianxiety Behavior when Administered Systemically to Ovariectomized Rats

“…ERa has been localized to the hypothalamus, an important brain region for sexual receptivity. E 2 -facilitated receptivity of rats is blocked by antisense oligonucleotides for ERa (not ERb), and does not occur in ERb (but does occur in ERa) knockout mice (Apostolakis et al, 2000;Ogawa et al, 1996Ogawa et al, , 1998Ogawa et al, , 1999. Further, ERa knockout mice are anovulatory, have dis- The mean (7SEM) number of punished licks made in the Vogel task of ovx rats coadministered vehicle (solid bars) or tamoxifen (striped bars) and vehicle, 17b-E 2 , COUM, or DPN 48 h before testing (n ¼ 7-10/condition).…”