Reduced prepubertal expression of progesterone receptor in the hypothalamus of female aromatase knockout mice

Abstract

Previous research using alpha-fetoprotein knockout and aromatase knockout (ArKO) female mice suggested that the developing hypothalamic mechanisms that later control feminine sexual behavior are protected prenatally from estradiol, whereas shortly after birth, they may be stimulated by this same sex hormone. In the present study, we found that the amount of progesterone receptor immunoreactivity (PR-ir) in the anteroventral periventricular nucleus and medial part of the medial preoptic nucleus was significantly lower in ArKO female mice than in wild-type (WT) females at several prepubertal ages including postnatal d 15 (P15), P15, P20, and P25 but not neonatally at P0, P5, or P10. Likewise, PR-ir in the lateral subdivision of the ventromedial hypothalamic nucleus was significantly lower at P25 in ArKO vs. WT female mice but not at earlier postnatal ages. PR-ir was consistently higher in male than in female WT mice in the anteroventral periventricular nucleus and medial preoptic nucleus over P0-P10 and in the ventromedial hypothalamic nucleus over P0-P20. In these brain regions across these latter ages, PR-ir in male ArKO mice was significantly lower than in WT males and resembled the values seen in WT females, confirming previous reports that estradiol formed in the developing male hypothalamus from testicular testosterone is responsible for male-typical levels of neural PR expression. Thus, estradiol induces both female- and male-typical expression of PR postnatally in the mouse hypothalamus. Future experiments will determine whether this estradiol-induced PR expression contributes to either female- or male-typical brain and behavioral differentiation.

Figure 1

Drawings taken from the mouse brain atlas of Paxinos and Franklin (24) showing the location of forebrain regions in which PR-ir cells were quantified (shaded areas in each panel) in the AVPv (A), MPOA (B). and VMH-L (C). The distance of each coronal brain slice in front of (+) or behind (−) bregma is given for each panel.

Figure 2

Representative photomicrographs show coronal sections of the MPOA with PR-ir cells in a WT female (A), an ArKO female (B), a WT male (C), and an ArKO male (D) at P10. V, Third ventricle. Scale bar, 40 μm.

Figure 3

The relative amount (mean ± sem) of PR-ir in the MPOA on P0, P5, P10, P15, P20, and P25 in male (M) and female (F) mice that were either WT or ArKO. *, Post hoc comparisons indicated a significant (P < 0.05) sex difference in WT mice at the ages indicated. Post hoc comparisons also indicated significant (P < 0.05) differences between WT vs. ArKO females (F over brackets) and between WT and ArKO males (M over brackets) at the ages shown.

Figure 4

The relative amount (mean ± sem) of PR-ir in the AVPv on P0, P5, P10, P15, P20, and P25 in male (M) and female (F) mice that were either WT or ArKO. *, Post hoc comparisons indicated a significant (P < 0.05) sex difference in WT mice at the ages indicated. Post hoc comparisons also indicated significant (P < 0.05) differences in WT vs. ArKO females (F over brackets) and between WT and ArKO males (M over brackets) at the ages shown.

Figure 5

The relative amount (mean ± sem) of PR-ir in the VMH-L on P0, P5, P10, P15, P20, and P25 in male (M) and female (F) mice that were either WT or ArKO. *, Post hoc comparisons indicated a significant (P < 0.05) sex difference in WT mice at the ages indicated. Post hoc comparisons also indicated significant (P < 0.05) differences in WT vs. ArKO females (F over brackets) and between WT and ArKO males (M over brackets) at the ages shown.