Role of the ERp57 protein (1,25D3-MARRS receptor) in murine mammary gland growth and development.

The protein disulfide isomerase ERp57 (GRp58/PDIA3/1,25D3-MARRS) has been implicated in a multitude of signaling pathways throughout the entire body. Most thoroughly studied for its protein-folding role, ERp57 has also been found to have multiple binding partners, and have significant effects on cellular growth. ERp57 has been studied n the context of several neurodegenerative disorders, metabolic conditions, and can be used as a prognosis marker in certain cancers. One role, as an alternate vitamin D binding receptor, has prompted research in tissues with known vitamin D activity, such as the intestine and bone. Vitamin D has been studied in relation to mammary gland growth and development, but it is not yet known if ERp57 plays an independent role in this tissue. In this study, ERp57 was knocked out in murine mammary gland epithelial cells of 30 4-week old mice. Several markers of mammary gland growth were measured, including number of terminal end buds (TEB), ductal coverage of the fat pad, and ductal extension. It was found the knockout animals had decreased numbers of TEBs (p = 0.019), and decreased ductal extension (p = 0.018) compared to wildtype animals, with no differences in gross body weight. Immunohistochemistry analysis of mammary glands showed ERp57 localized to the apical side of alveolar branches, and on leading edges of TEBs. These results provide further evidence for ERp57 functioning separately to the VDR, and further insights into the roles of ERp57.

Male risk taking, female odors, and the role of estrogen receptors.

Male risk-taking and decision making are affected by sex-related cues, with men making riskier choices and decisions after exposure to either women or stimuli associated with women. In non-human species females and, or their cues can also increase male risk taking. Under the ecologically relevant condition of predation threat, brief exposure of male mice to the odors of a sexually receptive novel female reduces the avoidance of, and aversive responses to, a predator. We briefly review evidence showing that estrogen receptors (ERs), ERα and ERß, are associated with the mediation of these risk taking responses. We show that ERs influence the production of the female odors that affect male risk taking, with the odors of wild type (ERαWT, ERßWT), oxytocin (OT) wildtype (OTWT), gene-deleted 'knock-out' ERß (ERßKO), but not ERαKO or oxytocin (OT) OTKO or ovariectomized (OVX) female mice reducing the avoidance responses of male mice to cat odor. We further show that administration of specific ERα and ERß agonists to OVX females results in their odors increasing male risk taking and boldness towards a predator. We also review evidence that ERs are involved in the mediation of the responses of males to female cues, with ERα being associated with the sexual and both ERß and ERα with the sexual and social mechanisms underlying the effects of female cues on male risk taking. The implications and relations of these findings with rodents to ERs and the regulation of human risk taking are briefly considered.

Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice.

Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERalpha) or beta (ERbeta) knockout (KO) mice show that long-term inactivation of ERalpha decreases, while inactivation of ERbeta increases, male aggression. Opposite effects were found in female alphaERKO and betaERKO mice. The role of acute activation of ERalpha or ERbeta in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERbeta selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: (1) effects of WAY-200070 on each sex and gonadal condition; (2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice, WAY-200070 increased agonistic behaviors such as pushing down the intruder and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERbeta mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERbeta in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERbeta. Thus, acute activation of ERbeta similarly mediates agonistic behavior in adult male and female CD-1 mice.