Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene

PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogene sis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a pa rt in development and oncogenesis and to uncover its normal physiological r ole, we generated mice lacking functional PEA3 by gene targeting in embryon ic stem cells, PEA3(-/-) mice arose from heterozygous crosses with the expe cted Mendelian frequency, revealing that PEA3 is dispensable for embryogene sis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce, PEA3 is expressed in several male sexual organs, but gross and histological analyses of the o rgans from PEA3-/- mice revealed no abnormalities, Spermatogenesis and sper miogenesis also appeared normal in mice homozygous for the PEA3 mutation, a nd their sperm were capable of fertilizing eggs in vitro. PEA(-/-) males en gaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA 3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-defic ient male mice, and the results of in vitro experiments revealed that the c orpus cavernosum isolated from PEA3 mutant males relaxed in response to ace tylcholine. Therefore, the infertility of PGA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysf unction, However, PEA3 mutant mice are phenotypically distinguishable From other knockout mice with such deficits and thus provide a unique model for Further investigation of male sexual dysfunction.