Characterization of infertile male mice with ampullar innervation defects resulting from targeting of the Evx1 gene.

摘要

Members of the Hox gene family of transcriptional regulators, in particular those located near the 5' end of the respective Hoxa and Hoxd clusters as well as Evx1 and Evx2 located upstream of the Hoxa and Hoxd clusters respectively, are known to play roles in neuronal and reproductive development. To gain insight into Evx1 function, we created a novel targeted allele of Evx1 (Evx1 H) lacking all DNA binding and carboxy-terminal sequences. Homozygous Evx1H/H females are unaffected, while Evx1H/H males are uniformly infertile. Evx1H/H males fail to produce a seminal plug after mating, but retain normal sperm production and function as assessed by in-vitro fertilization. Gross dissection and histological examination support normal development of reproductive organs, except for accumulation of secretions resulting in a profound distention of seminal vesicles, vasa deferentia, epididymides and ampulla after puberty. The accumulation of secretions within the ampulla is accompanied by degeneration of the lumenal epithelial cells. Evx1H/H males vasectomized before puberty are rescued from these phenotypes. In-situ hybridization and immunohistochemistry demonstrate that Evx1 is normally expressed in the testis, epididymis, and ampulla during development however, Evx1-positive neurons concentrated within the ampulla are absent in Evx1H/H homozygous males. Molecular expression analyses reveal elevated levels of En1 and Wnt7a transcription specifically within the ampulla of Evx1 H/H males possibly contributing to a neuronal phenotype. Our results are consistent with the concept that Evx1 function is essential for proper establishment and development of neuronal cells in the ampulla essential to the ejaculatory process.