Article

Male infertility, impaired sperm motility, and hydrocephalus in mice deficient in sperm-associated antigen 6.

Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 10/2002; 22(17):6298-305. DOI: 10.1128/MCB.22.17.6298-6305.2002
Source: PubMed

ABSTRACT Gene targeting was used to create mice lacking sperm-associated antigen 6 (Spag6), the murine orthologue of Chlamydomonas PF16, an axonemal protein containing eight armadillo repeats predicted to be important for flagellar motility and stability of the axoneme central apparatus. Within 8 weeks of birth, approximately 50% of Spag6-deficient animals died with hydrocephalus. Spag6-deficient males surviving to maturity were infertile. Their sperm had marked motility defects and was morphologically abnormal with frequent loss of the sperm head and disorganization of flagellar structures, including loss of the central pair of microtubules and disorganization of the outer dense fibers and fibrous sheath. We conclude that Spag6 is essential for sperm flagellar motility and that it is important for the maintenance of the structural integrity of mature sperm. The occurrence of hydrocephalus in the mutant mice also implicates Spag6 in the motility of ependymal cilia.

0 Followers
 · 
193 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tssk4 belongs to the Testis Specific Serine/threonine protein Kinase family, members of which play an important role in spermatogenesis and/or spermiogenesis. Several Tssk family proteins have been extensively studied. However, the exact function of Tssk4 remains unclear. A Tssk4 knockout mouse model was generated and the males were subfertile due to seriously decreased sperm motility. The ultrastructure of the Tssk4(-/-) sperm tail is disorganized at the midpiece-principal piece junction, leading to a severe bend in the sperm flagellum. One or more axonemal microtubule doublets are absent and the midpiece is fused with the principal piece. Furthermore, we identified the association between Tssk4 and Odf2, a prominent cytoskeletal protein of the outer dense fiber (ODF) in sperm flagellum. Tssk4 can change the phosphorylation state of Odf2 and conversely Odf2 potentiates the autophosphorylation activity of Tssk4. These findings reveal that Tssk4 is required for maintaining the structural integrity of sperm flagellum and male fertility.
    Molecular Human Reproduction 10/2014; DOI:10.1093/molehr/gau097 · 3.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian SPAG6 protein is localized to the axoneme central apparatus, and it is required for normal flagella and cilia motility. Recent studies demonstrated that the protein also regulates ciliogenesis and cilia polarity in the epithelial cells of brain ventricles and trachea. Motile cilia are also present in the epithelial cells of the middle ear and Eustachian tubes, where the ciliary system participates in the movement of serous fluid and mucus in the middle ear. Cilia defects are associated with otitis media (OM), presumably due to an inability to efficiently transport fluid, mucus and particles including microorganisms. We investigated the potential role of SPAG6 in the middle ear and Eustachian tubes by studying mice with a targeted mutation in the Spag6 gene. SPAG6 is expressed in the ciliated cells of middle ear epithelial cells. The orientation of the ciliary basal feet was random in the middle ear epithelial cells of Spag6-deficient mice, and there was an associated disrupted localization of the planar cell polarity (PCP) protein, FZD6. These features are associated with disordered cilia orientation, confirmed by scanning electron microscopy, which leads to uncoordinated cilia beating. The Spag6 mutant mice were also prone to develop OM. However, there were no significant differences in bacterial populations, epithelial goblet cell density, mucin expression and Eustachian tube angle between the mutant and wild-type mice, suggesting that OM was due to accumulation of fluid and mucus secondary to the ciliary dysfunction. Our studies demonstrate a role for Spag6 in the pathogenesis of OM in mice, possibly through its role in the regulation of cilia/basal body polarity through the PCP-dependent mechanisms in the middle ear and Eustachian tubes.
    PLoS ONE 11/2014; 9(11):e112879. DOI:10.1371/journal.pone.0112879 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mouse mutants that show effects on sperm head shape, the sperm tail (flagellum), and motility were analysed in a systematic way. This was achieved by grouping mutations in the following classes: manchette, acrosome, Sertoli cell contact, chromatin remodelling, and mutations involved in complex regulations such as protein (de)phosphorylation and RNA stability, and flagellum/motility mutations. For all mutant phenotypes, flagellum function (motility) was affected. Head shape, including the nucleus, was also affected in spermatozoa of most mouse models, though with considerable variation. For the mutants that were categorized in the flagellum/motility group, generally normal head shapes were found, even when the flagellum did not develop or only poorly so. Most mutants are sterile, an occasional one semi-sterile. For completeness, the influence of the sex chromosomes on sperm phenotype is included. Functionally, the genes involved can be categorized as regulators of spermiogenesis. When extrapolating these data to human sperm samples, in vivo selection for motility would be the tool for weeding out the products of suboptimal spermiogenesis and epididymal sperm maturation. The striking dependency of motility on proper sperm head development is not easy to understand, but likely is of evolutionary benefit. Also, sperm competition after mating can never act against the long-term multi-generation interest of genetic integrity. Hence, it is plausible to suggest that short-term haplophase fitness i.e., motility, is developmentally integrated with proper nucleus maturation, including genetic integrity to protect multi-generation fitness. We hypothesize that, when the prime defect is in flagellum formation, apparently a feedback loop was not necessary as head morphogenesis in these mutants is mostly normal. Extrapolating to human-assisted reproductive techniques practice, this analysis would supply the arguments for the development of tools to select for motility as a continuous (non-discrete) parameter. © 2014 American Society of Andrology and European Academy of Andrology.
    Andrology 12/2014; DOI:10.1111/andr.300 · 3.37 Impact Factor

Full-text (2 Sources)

Download
33 Downloads
Available from
May 21, 2014