Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO)

Abstract

Male mice with a knockout of the estrogen receptor (ER)-␣ gene, a ligand-activated transcription factor, showed reduced levels of intromissions and no ejaculations whereas simple mounting behavior was not affected. In contrast, all components of sexual behaviors were intact in male mice lacking the novel ER-␤ gene. Here we measure the extent of phenotype in mice that lack both ER-␣ and ER-␤ genes (␣␤ERKO). ␣␤ERKO male mice did not show any components of sexual behaviors, including simple mounting behavior. Nor did they show ultrasonic vocalizations during behavioral tests with receptive female mice. On the other hand, reduced aggressive behaviors of ␣␤ERKO mice mimicked those of single knockout mice of ER-␣ gene (␣ERKO). They showed reduced levels of lunge and bite aggression, but rarely showed offensive attacks. Thus, either one of the ERs is sufficient for the expression of simple mounting in male mice, indicating a redundancy in function. Offensive attacks, on the other hand, depend specifically on the ER-␣ gene. Different patterns of natural behaviors require different patterns of functions by ER genes.testosterone ͉ mounts ͉ intromissions ͉ ejaculation ͉ aggression I ntracellular estrogen receptors (ERs) play key roles in the neuroendocrine regulation of reproduction. Binding of ovarian steroid, estradiol, to ERs in female rodents triggers a series of molecular and neurochemical processes that lead to the induction of lordosis behavior, an essential behavioral component for successful reproduction (1). Normal expression of male reproductive behaviors also may depend on activation of ER, because the male gonadal steroid, testosterone, acts not only through androgen receptors (ARs) in its original form or 5␣-reduced form (dihydrotestosterone), but also through ERs after being aromatized to estradiol.Two types of ERs, ER␣ and ER␤, which bind to estradiol with a similar affinity, are identified in the brain (2-4). This field of work is well enough developed that we can attempt to move beyond the classical Beadle and Tatum ''one gene, one enzyme'' formulation, to discover patterns of gene activation influencing patterns of behavior.In knockout (KO) mice that lack the gene for either ER␣ (␣ERKO) or ER␤ (␤ERKO) individually (5, 6), male sexual behaviors are only partially disrupted or even virtually normal. ␣ERKO mice, although they rarely ejaculated and were infertile, showed almost normal levels of mounts and just reduced levels of intromissions (7). In contrast, all three components of sexual behaviors were present and robust in intact ␤ERKO males (8). Because earlier findings indicated some unique ovarian phenotype in double KO mice compared with either ␣ERKO or ␤ERKO (9), it was necessary to determine what pattern of behavioral deficits would appear in KO mice that lack both ER␣ and ER␤ genes (␣␤ERKO).In aromatase KO (ArKO) male mice sexual behaviors are strongly modified including the reduction of mount frequency and the prolonged mount latency (10). However, male ArKO mice are known to be fertile (11). It i...

Sexual behavior in male rodents

“…Pubertal males lacking ERβ (ERβKO) acquired the ability to ejaculate later than did WT males, but were otherwise normal (Temple et al, 2003). Males lacking both ERs did not copulate at all when gonadally intact (Ogawa et al, 2000). However, apomorphine was able to stimulate mounting in most animals and intromitting in half; none ejaculated (described in BurnsCusato et al, 2004).…”

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

“…The masculinization and defeminization of male sexual behavior in rodents are traditionally believed to rely on the conversion of androgens to estrogens and the subsequent activation of ERs during the perinatal period, a hypothesis most recently supported by data from mice deficient in either aromatase or ERs (Ogawa et al, 2000;Matsumoto et al, 2003;Ogawa et al, 1997). However, newborn male rats administered an aromatase inhibitor retain masculine sexual behaviors (Dominguez-Salazar et al, 2002), while genetically produced AR knockout mice (ARKO) show less masculine sexual behavior (Sato et al, 2004), suggesting that ARs are also involved in male sexual behavior.…”

“…The aromatization hypothesis also seems to hold for the development of some sexual and nonsexual rodent behaviors. Defeminization of rat sexual behavior, as measured by the proclivity to show lordosis (the female posture of sexual receptivity), and masculinization of aggressive behavior in rodents are largely controlled by estrogenic metabolites of T acting on ERs (Olsen, 1979;Vreeburg et al, 1977;Ogawa et al, 2000;Scordalakes and Rissman, 2004).…”

Genetic basis of male sexual behavior

“…Conditional knock-out or knock-in techniques may be used in vertebrates to examine whether a gene plays primarily a developmental role. For example, genetic ablation of the estrogen ␣ and ␤ receptor types results in the complete loss of expression of male sexual behavior in mouse (Ogawa et al, 2000). Whether this is due to a developmental or functional defect could be examined by eliminating the receptor in the adult.…”

“…An example, mentioned above, is the genetic ablation in mouse of the estrogen ␣ and ␤ receptor types, which results in the loss of expression of male sexual behavior (Ogawa et al, 2000).…”