Generation and reproductive phenotypes of mice lacking estrogen receptor beta

Estrogens influence the differentiation and maintenance of reproductive tis sues and affect lipid metabolism and bone remodeling. Two estrogen receptor s (ERs) have been identified to date, ER alpha and ER beta. We previously g enerated and studied knockout mice lacking estrogen receptor alpha and repo rted severe reproductive and behavioral phenotypes including complete infer tility of both male and female mice and absence of breast tissue developmen t. Here we describe the generation of mice lacking estrogen receptor beta ( ER beta -/-) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly a nd histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ER beta -/- mice lack normal ER beta RNA and protein. Breeding experiments with young, sexually mature fema les show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate n ormally. Young, sexually mature male mice show no overt abnormalities and r eproduce normally. Older mutant males display signs of prostate and bladder hyperplasia, Our results indicate that ER beta is essential for normal ovu lation efficiency but is not essential for female or male sexual differenti ation, fertility, or lactation. Future experiments are required to determin e the role of ER beta in bone and cardiovascular homeostasis.