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

Estrogen receptors (ERs) are expressed in the thymus of both males and fema les, but their role in thymic development and function is unclear. To deter mine whether ER alpha plays a role in thymic function of either males or fe males, we compared thymuses of male and female wild-type (WT) and ER alpha knockout (alpha ERKO) mice from birth to adulthood. Although thymic size wa s 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 mi ce had significant (30-55%) reductions in thymic weight. Morphometric analy sis revealed a reduction in thymic medullary areas in adult ERKO mice compa red with age-matched WT controls that paralleled thymic involution, There w ere changes in relative percentages of CD4(+) and CD4(+)CD8(+) T-cells, and large decreases (70-80%) in overall absolute numbers of CD4(+) and CD4(+)C D8(+) T-cells, Serum corticosterone and testosterone levels were not differ ent in either neonatal or adult male WT or alpha ERKO mice, and serum level s of 17 beta-estradiol (E-2) were similar in neonatal WT and alpha ERKO mal es, indicating that increases in these thymolytic hormones are not responsi ble for the decreased thymic weight in alpha ERKO males. Additionally, dela yed-type hypersensitivity was significantly in creased in male alpha ERKO m ice 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 postn atal function of the female thymus gland. The similar results obtained in m ales demonstrate a role for the E-2/ER alpha signaling system in the male t hymus and emphasize that estrogens play a more critical role in the male th an previously realized.