Estrogen receptor-alpha is required by the supporting somatic cells for spermatogenesis

The gene for estrogen receptor-alpha (ERalpha) was disrupted in embryonic stem cells by homologous recombination and these cells were used to generate mice with a targeted mutation in the ERalpha gene (alphaERKO mice). It was found that males homozygous for the mutation are infertile, indicating that estrogen signaling through this nuclear hormone receptor is required for male reproductive function. Although spermatogenesis appears normal in juvenile and young adult alphaERKO mice, the sperm produced are unable to fertilize eggs in vitro. To determine whether ERalpha is required by somatic or germ cells in the male reproductive tract, we transplanted germ cells from homozygous mutant (ERalpha(-/-)) males to the testes of wild-type (ERalpha(+/+)) males depleted of germ cells by busulfan treatment. The recipients ('surrogate fathers') sired offspring heterozygous for the mutation (ERalpha(+/-)) and carrying the coat-color marker of the infertile donor males. This indicated that ERalpha(-/-) germ cells are able to produce sperm competent to fertilize when they are supported by ERalpha(+/+) somatic cells. When ERalpha(+/-) offspring produced by germ cell transplantation were mated to produce ERalpha(-/-) males, these mice were found to have the same phenotype as originally reported for alphaERKO males. These studies showed that male germ cells do not require ERalpha for regulation of their own genes for development and function, and strongly imply that somatic cells of the male reproductive tract require ERalpha to support the production of sperm that are capable of fertilization.