Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system

Abstract

Motile cilia line the efferent ducts of the mammalian male reproductive tract. Several recent mouse studies have demonstrated that a reduced generation of multiple motile cilia in efferent ducts is associated with obstructive oligozoospermia and fertility issues. However, the sole impact of efferent duct cilia dysmotility on male infertility has not been studied so far either in mice or human. Using video microscopy, histological- and ultrastructural analyses, we examined male reproductive tracts of mice deficient for the axonemal motor protein DNAH5: this defect exclusively disrupts the outer dynein arm composition of motile cilia but not the ODA composition and motility of sperm flagella. These mice have immotile efferent duct cilia that lack outer dynein arms, which are essential for ciliary beat generation. Furthermore, they show accumulation of sperm in the efferent duct. Notably, the ultrastructure and motility of sperm from these males are unaffected. Likewise, human individuals with loss-of-function DNAH5 mutations present with reduced sperm count in the ejaculate (oligozoospermia) and dilatations of the epididymal head but normal sperm motility, similar to DNAH5 deficient mice. The findings of this translational study demonstrate, in both mice and men, that efferent duct ciliary motility is important for male reproductive fitness and uncovers a novel pathomechanism distinct from primary defects of sperm motility (asthenozoospermia). If future work can identify environmental factors or defects in genes other than DNAH5 that cause efferent duct cilia dysmotility, this will help unravel other causes of oligozoospermia and may influence future practices in genetic and fertility counseling as well as ART.

Primary Ciliary Dyskinesia

“…38 In males this is attributable to impaired sperm motility as the structure of sperm flagella resembles the structure of the 9 þ 2 motile cilia in the airways and to impaired ciliary motility in the efferent duct. 39 There is some genetic variation. As an example HYDIN-mutant sperm cells are predominantly immotile.…”

Bi‐allelic mutations in MCIDAS and CCNO cause human infertility associated with abnormal gamete transport

“…Furthermore, motile cilia have undoubtedly been associated with human reproduction. 7,8,21 Recently, we identified biallelic mutations in SPAG6 and RSPH3 in two infertile PCD patients with severe asthenoteratospermia characterized by multiple flagellar malformations and axonemal defects. 19 In this study, we identified a novel homozygous LOF mutation in MCIDAS in a male subject with PCD and idiopathic OA and a homozygous LOF mutation in CCNO in a female subject with PCD and potential ciliary dysfunction of the oviduct.…”

“…5 Therefore, ciliarelated pathogenic variations always cause functional abnormalities of the sperm flagellum and/or reproductive tract. [6][7][8] As a result, the majority of males and half of the females with PCD suffer infertility. 9 To date, pathogenic variants in over 40 genes have been reported to cause PCD, while mutations in these genes are responsible for only ~75% of PCD cases.…”

“…15,16 Especially, in axonemal outer dynein arm (ODA) defects, Dnah5 deficiency can cause the dysfunction of EDs motile cilia in mice, and DNAH5-mutated males present obstructive oligozoospermiaassociated infertility. 8 However, despite extensive research on MCIDAS and CCNO and increasing functional understanding of EDs and oviducts, studies on MCIDAS-and CCNO-mutated EDs and oviducts in humans are limited.…”

Current and Future Treatments in Primary Ciliary Dyskinesia

“…Consequently, up to half of all patients with PCD have a situs inversus or situs ambiguous due to randomization of the left–right body asymmetry [ 7 ]. Similarly, the structure of the flagella on sperm cells and the cilia lining of the fallopian tubes and vasa deferentia share many components with respiratory cilia, and male (often) and female (less frequently) infertility can occur [ 8 , 9 ]. The reduced generation of multiple motile cilia was associated with hydrocephalus, probably due to dysfunction of ependymal cilia motility [ 5 , 10 ].…”