Normal development of thymus in male and female mice requires estrogen/estrogen receptor-α signaling pathway

Estrogen receptors (ERs) are expressed in the thymus of both males and females, but their role in thymic development and function is unclear. To determine whether ER alpha plays a role in thymic function of either males or females, we compared thymuses of male and female wild-type (WT) and ER alpha knockout (alpha ERKO) mice from birth to adulthood. Although thymic size was similar in both male and female WT and alpha ERKO mice at birth (d0), by postnatal d5 and at all subsequent ages, both male and female alpha ERKO mice had significant (30-55%) reductions in thymic weight. Morphometric analysis revealed a reduction in thymic medullary areas in adult ERKO mice compared with age-matched WT controls that paralleled thymic involution, There were changes in relative percentages of CD4(+) and CD4(+)CD8(+) T-cells, and large decreases (70-80%) in overall absolute numbers of CD4(+) and CD4(+)CD8(+) T-cells, Serum corticosterone and testosterone levels were not different in either neonatal or adult male WT or alpha ERKO mice, and serum levels of 17 beta-estradiol (E-2) were similar in neonatal WT and alpha ERKO males, indicating that increases in these thymolytic hormones are not responsible for the decreased thymic weight in alpha ERKO males. Additionally, delayed-type hypersensitivity was significantly in creased in male alpha ERKO mice compared with WT mice. In summary, ER alpha deficiency does not inhibit initial differentiation or fetal thymic development, but the absence of ER alpha results in marked decreases in thymic size in both sexes during the postnatal period. These results are the first direct demonstration that the E-2/ER alpha signaling system is necessary for maintenance of normal postnatal function of the female thymus gland. The similar results obtained in males demonstrate a role for the E-2/ER alpha signaling system in the male thymus and emphasize that estrogens play a more critical role in the male than previously realized.