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Sex differences in progesterone receptor immunoreactivity in neonatal mouse brain depend on estrogen receptor alpha
C K Wagner1, J L Pfau, G J De Vries
1Center for Neuroendocrine Studies, Neuroscience and Behavior Program and Department of Psychology, University of Massachusetts, Tobin Hall, Box 37720, Amherst, Massachusetts 01003, USA. cwagner@psych.umass.edu
Insights
Estrogen receptor alpha (ER alpha) influences brain sexual differentiation. In neonatal mice, ER alpha activates progesterone receptor expression in males, potentially increasing brain sensitivity to progesterone and guiding sex-specific development.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Sex differences in brain development are influenced by hormones.
- Progesterone receptors (PR) in the medial preoptic nucleus (MPN) show sex-based expression differences around birth in rats.
- Estrogen receptors (ER) activation is implicated in these sex differences.
Purpose of the Study:
- To investigate the role of estrogen receptor alpha (ER alpha) in mediating sex differences in progesterone receptor (PR) expression in the neonatal mouse brain.
- To determine if ER alpha influences PR immunoreactivity (PRir) in specific brain regions, such as the MPN and ventromedial nucleus.
Main Methods:
- Comparison of PRir levels in the brains of male and female neonatal mice.
- Utilizing genetically modified mice lacking a functional ER alpha gene (knockout) alongside wild-type controls.
- Immunohistochemical analysis to quantify PRir in the MPN, ventromedial nucleus, and neocortex.
Main Results:
- Neonatal males exhibit significantly higher PRir in the MPN and ventromedial nucleus compared to females.
- PRir expression in these brain regions is dependent on the presence of functional ER alpha.
- PRir levels in the neocortex are not affected by ER alpha gene disruption, indicating region-specific effects.
Conclusions:
- Estrogen receptor alpha plays a critical role in the sexual differentiation of the brain.
- ER alpha-mediated induction of PR may enhance progesterone sensitivity in specific regions of the developing male brain.
- This mechanism likely contributes to the establishment of sex-specific neural circuits and behaviors.
Abstract:
Around the time of birth, male rats express higher levels of progesterone receptors in the medial preoptic nucleus (MPN) than female rats, suggesting that the MPN may be differentially sensitive to maternal hormones in developing males and females. Preliminary evidence suggests that this sex difference depends on the activation of estrogen receptors around birth. To test whether estrogen receptor alpha (ER alpha) is involved, we compared progesterone receptor immunoreactivity (PRir) in the brains of male and female neonatal mice that lacked a functional ER alpha gene or were wild type for the disrupted gene. We demonstrate that males express much higher levels of PRir in the MPN and the ventromedial nucleus of the neonatal mouse brain than females, and that PRir expression is dependent on the expression of ER alpha in these regions. In contrast, PRir levels in neocortex are not altered by ER alpha gene disruption. The results of this study suggest that the induction of PR via ER alpha may render specific regions of the developing male brain more sensitive to progesterone than the developing female brain, and may thereby underlie sexual differentiation of these regions.