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.

Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse

“…SLC26A3 is known to interact with the CFTR channel, and a physical and functional interaction between SLC26A3 and the sodium/hydrogen antiporter 3, NHE3, was also reported in both the intestine and in the male reproductive system (Hihnala et al, ; Lamprecht et al, ; Melvin, Park, Richardson, Schultheis, & Shull, ; Musch, Arvans, Wu, & Chang, ). Importantly, Wang and collaborators recently showed that NHE3‐deficient mice display several defects in the ultrastructure of the epididymis and the vas deferens, as well as significant reduction of CFTR protein levels in these structures, ultimately leading to male infertility (Wang et al, ). These results corroborate the hypothesis of a functional multi‐channel protein complex, CFTR/SLC26A3/NHE3, involved in the regulation of ion microenvironment that would be required for normal cytoarchitecture of the male reproductive tract.…”

Genetics of the congenital absence of the vas deferens

“…Indeed, these authors showed that the adult male mouse SLC9A3-/develops obstructive azoospermia due to structural and functional abnormalities of the efferent ductules with long-term progressive atrophy of the vas deferens and seminal vesicles (Wu et al 2019;Chiang et al 2019). Remarkably, authors observed a drastic decrease in CFTR in the epididymis and vas deferens in these SLC9A3-KO mice suggesting interdependent roles of the two genes in iCBAVD determinism (Wang et al 2017). However, despite these very enlightening observations on the role of SLC9A3 in the physiology of the reproductive tract of male mice, the relationship between the loss of a copy of this gene and iCBAVD in humans is still poorly understood.…”

SLC9A3 Protein Is Critical for Acrosomal Formation in Postmeiotic Male Germ Cells

“…SLC9A3 is one of nine plasma membrane Na + /H + exchangers (SLC9A1-9) and is expressed on the apical membranes of the intestinal epithelium, renal proximal tubule, epididymis, and vas deferens [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. The widely known functions of SLC9A3 are ion homeostasis regulation through Na + and water absorption, and it often functionally couples with transepithelial Cl − /HCO 3 − exchangers in the intestine [ 8 ].…”

“…Through oligonucleotide array-based comparative genomic hybridization (array-CGH), we identified the loss of one Slc9a3 allele in 28.57% of Taiwanese men with CBAVD [ 23 ]. However, loss of SLC9A3 causes obstructive azoospermia and testicular atrophy [ 6 ]. Colleagues’ and our own studies have indicated that Slc9a3 −/− adult male mice are completely infertile compared with wild-type (WT) and heterozygous mice [ 6 , 15 ].…”

“…However, loss of SLC9A3 causes obstructive azoospermia and testicular atrophy [ 6 ]. Colleagues’ and our own studies have indicated that Slc9a3 −/− adult male mice are completely infertile compared with wild-type (WT) and heterozygous mice [ 6 , 15 ]. Slc9a3 −/− male mice possess an abnormally dilated lumen in the rete testis and calcification in the efferent ductules.…”