title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) and are associated with congenital bilateral absence of the vas deferens (CBAVD), which is the major cause of infertility in male patients with CF. However, most Taiwanese patients with CBAVD do not carry major CFTR mutations. Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene. SLC9A3 is a Na+/H+ exchanger, and depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules. Furthermore, SLC9A3 interacts with CFTR in the pancreatic duct and functions as a genetic modifier of CF. However, SLC9A3 function and its relation to CFTR expression in the male reproductive tract in vivo remain elusive. In the present study, we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice. Adult Slc9a3-/- mice showed not only significantly decreased epididymis and vas deferens weight but also increased testis weight. Furthermore, Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract. Ultrastructural analysis of the epithelium in Slc9a3-/-epididymis and vas deferens displayed disorganized and reduced number of stereocilia and numerous secretory apparatuses. Our data revealed that interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract. The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations.
authors.affiliation: Department of Chemistry, Fu Jen Catholic University, New Taipei City, Taiwan.|Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Yi-No
authors.initials: YN
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Fu Jen Catholic University, New Taipei City, Taiwan.|Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.|Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Chiao-Yin
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.|Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Han-Sun
authors.initials: HS
authors.lastname: Chiang
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009845:Oligospermia / Q000235:genetics* / Q000473:pathology; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D012141:Respiratory Tract Infections / Q000235:genetics* / Q000473:pathology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*
chemical_list: C000613385:SLC9A3 protein, human; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator