title: Epididymal expression of the forkhead transcription factor Foxi1 is required for male fertility.
abstract: An essential aspect of male reproductive capacity is the immediate availability of fertilization-ready spermatozoa. To ensure this, most mammals rely on post-testicular sperm maturation. In epididymis, germ cells are matured and stored in a quiescent state that readily can be altered to produce active spermatozoa. This depends on active proton secretion into the epididymal lumen. We have identified Foxi1 as an important regulator of gene expression in narrow and clear cells-the major proton secretory cells of epididymal epithelia. Foxi1 appears to be required for the expression of the B1-subunit of the vacuolar H+ -ATPase proton pump and for carbonic anhydrase II as well as the chloride/bicarbonate transporter pendrin. Using transfection experiments, we have identified a Foxi1 binding cis-element in the ATP6V1B1 (encoding the B1-subunit) promoter that is critical for reporter gene activation. When this site is mutated to eliminate Foxi1 binding, activation is also abolished. As a consequence of defect Foxi1-dependent epididymal sperm maturation, we demonstrate that spermatozoa from Foxi1 null males fail to reach the female genital tract in sufficient number to allow fertilization.
authors.affiliation: Center of Medical Genetics, Institute of Biomedicine, Göteborg University, Göteborg, Sweden.
authors.forename: Sandra Rodrigo
authors.initials: SR
authors.lastname: Blomqvist
authors.forename: Hilmar
authors.initials: H
authors.lastname: Vidarsson
authors.forename: Olle
authors.initials: O
authors.lastname: Söder
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism; D019556:COS Cells; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D004822:Epididymis / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D013094:Spermatozoa / Q000502:physiology; D000076988:Sulfate Transporters; D015533:Transcriptional Activation; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D051858:Forkhead Transcription Factors; C508689:Foxi1 protein, mouse; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; C480628:Atp6v1b1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D024402:Carbonic Anhydrase II