MOLECULAR BASIS OF MAMMALIAN SPERM MOTILITY

Summary

Principal Investigator: JEROME STRAUSS
Abstract: DESCRIPTION (provided by applicant): The assembly of the sperm flagellum, the coordination of flagella formation with other events during spermiogenesis, the maintenance of flagellar structural integrity, and the regulation of the flagellar power stroke and waveform are poorly understood at the molecular level. The long-term goal of this research is to characterize regulatory proteins of the mammalian sperm axoneme, and to identify their roles in governing flagellar structure and activity. This knowledge will provide a molecular framework for understanding sperm motility defects causing male infertility and the function of "9+2" cilia in general. Four specific aims are proposed based upon our observations suggesting bi-functional roles for the Pf20 gene. Pf20 encodes two proteins, the 71 kDa PF20I, localized to the axoneme central apparatus, and a second protein transcribed from a testis-specific promoter, 35 kDa PF20s, which contains the C-terminus of PF20I, but is localized to the germ cell nucleus. PF20I is produced meiotically, PF20s accumulates post-meiotically. Highly chimeric mice with a mutated Pf20 allele that affects PF20s expression have a phenotype of severe oligospermia and sperm axonemal defects. These observations suggest that PF20I and PF20s may have distinct roles. PF20I in the axoneme interacts with SPAG6, apparently facilitating assembly or imparting stability to the sperm flagellar axoneme. PF20s interacts with a testis-specific serine threonine kinase, TSSK-2, and a chromosome-binding protein in the nucleus, meiosis induced gene 1 (MEIG1). Experiments will be conducted to establish that Pf20 is a unique gene that is involved in the formation/stability of an organelle (the axoneme) essential for sperm function (motility) and differentiation events (gene expression). The hypotheses to be tested include: 1) that PF20I plays an important role in sperm motility such that male mice lacking PF20I will be infertile due to a severe sperm motility defect due to abnormalities in the assembly or structural integrity of the sperm axoneme;2) that PF20s is required for normal post-meiotic sperm development, acting in the nucleus to regulate gene expression such that mice deficient in PF20s will be sterile due to post-meiotic spermatogenic failure;3) that TSSK-mediated phosphorylation regulates PF20s function;and 4) that PF20 mutations cause abnormalities in human spermatogenesis as well as primary ciliary dyskinesia. The latter hypothesis is supported by the discovery of oligospermic males heterozygous for mutations that would affect PF20s expression.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Deficiency of SPAG16L causes male infertility associated with impaired sperm motility
    Zhibing Zhang
    Center for Research on Reproduction and Women s Health, University of Pennsylvania Medical Center, Philadelphia 19104, USA
    Biol Reprod 74:751-9. 2006
  2. pmc Germ cell-specific disruption of the Meig1 gene causes impaired spermiogenesis in mice
    M E Teves
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Andrology 1:37-46. 2013
  3. pmc Genetic variation in SPAG16 regions encoding the WD40 repeats is not associated with reduced sperm motility and axonemal defects in a population of infertile males
    David R Nagarkatti-Gude
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    BMC Urol 12:27. 2012
  4. pmc Mouse RC/BTB2, a member of the RCC1 superfamily, localizes to spermatid acrosomal vesicles
    Jiannan Wang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America
    PLoS ONE 7:e39846. 2012
  5. pmc Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival
    Maria Eugenia Teves
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Am J Respir Cell Mol Biol 48:765-72. 2013
  6. pmc Targeted deletion of Tssk1 and 2 causes male infertility due to haploinsufficiency
    Bingfang Xu
    Department of Cell Biology, Center for Research in Contraceptive and Reproductive Health, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
    Dev Biol 319:211-22. 2008
  7. pmc TSKS concentrates in spermatid centrioles during flagellogenesis
    Bingfang Xu
    Department of Cell Biology, Center for Research in Contraceptive and Reproductive Health, University of Virginia, Charlottesville, VA 22908, USA
    Dev Biol 319:201-10. 2008
  8. pmc Phosphorylation of mouse sperm axoneme central apparatus protein SPAG16L by a testis-specific kinase, TSSK2
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Biol Reprod 79:75-83. 2008
  9. ncbi A heterozygous mutation disrupting the SPAG16 gene results in biochemical instability of central apparatus components of the human sperm axoneme
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Biol Reprod 77:864-71. 2007
  10. ncbi Accelerated mortality from hydrocephalus and pneumonia in mice with a combined deficiency of SPAG6 and SPAG16L reveals a functional interrelationship between the two central apparatus proteins
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Cell Motil Cytoskeleton 64:360-76. 2007

Scientific Experts

  • Zhibing Zhang
  • JEROME STRAUSS
  • David R Nagarkatti-Gude
  • Bingfang Xu
  • Scott C Henderson
  • Jiannan Wang
  • M E Teves
  • Maria Eugenia Teves
  • Maria E Teves
  • Xuening Shen
  • Kathleen A Lesich
  • Elizabeth Anne Kiselak
  • Celso Silva
  • John C Herr
  • Silvia Pulido
  • Laura Digilio
  • Kula N Jha
  • Zhonglin Hao
  • Craig Urekar
  • Charles J Flickinger
  • J Song
  • D R Nagarkatti-Gude
  • Bruce K Rubin
  • Mark Subler
  • Fadi N Salloum
  • Richard M Costanzo
  • K N Jha
  • Jamal Zweit
  • J C Herr
  • Gobalakrishnan Sundaresan
  • Frank D Corwin
  • J A Foster
  • Elena Moretti
  • Giulia Collodel
  • Lori D Hill
  • Rex A Hess
  • Michela Geminiani
  • Ruth Jaimez
  • David Roberto Gude
  • Jingmei Song
  • Steven L Brody
  • Courtney B Kelsch
  • Kristen L Ponichter
  • Charles B Lindemann
  • Lisa Salvador
  • Jennifer R Wood
  • Igor Kostetskii
  • Carmen J Williams

Detail Information

Publications15

  1. ncbi Deficiency of SPAG16L causes male infertility associated with impaired sperm motility
    Zhibing Zhang
    Center for Research on Reproduction and Women s Health, University of Pennsylvania Medical Center, Philadelphia 19104, USA
    Biol Reprod 74:751-9. 2006
    ..The sperm defect is consistent with the motility phenotype of the Pf20 mutants of Chlamydomonas, but morphologically different in that the mutant algal axoneme lacks the central apparatus...
  2. pmc Germ cell-specific disruption of the Meig1 gene causes impaired spermiogenesis in mice
    M E Teves
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Andrology 1:37-46. 2013
    ..Our results indicate that MEIG1 regulates spermiogenesis through effects in germ cells alone, and that the Meig1 gene must be active during a discrete period in spermatogenesis after which it is dispensable...
  3. pmc Genetic variation in SPAG16 regions encoding the WD40 repeats is not associated with reduced sperm motility and axonemal defects in a population of infertile males
    David R Nagarkatti-Gude
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    BMC Urol 12:27. 2012
    ..We have also reported that a heterozygous mutation of the human SPAG16 gene reduces stability of the sperm axonemal central apparatus...
  4. pmc Mouse RC/BTB2, a member of the RCC1 superfamily, localizes to spermatid acrosomal vesicles
    Jiannan Wang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America
    PLoS ONE 7:e39846. 2012
    ..Since RCC1 domains associate with Ran, a small GTPase that regulates molecular trafficking, it is possible that RC/BTB2 plays a role in transporting proteins during acrosome formation...
  5. pmc Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival
    Maria Eugenia Teves
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Am J Respir Cell Mol Biol 48:765-72. 2013
    ..We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance...
  6. pmc Targeted deletion of Tssk1 and 2 causes male infertility due to haploinsufficiency
    Bingfang Xu
    Department of Cell Biology, Center for Research in Contraceptive and Reproductive Health, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
    Dev Biol 319:211-22. 2008
    ....
  7. pmc TSKS concentrates in spermatid centrioles during flagellogenesis
    Bingfang Xu
    Department of Cell Biology, Center for Research in Contraceptive and Reproductive Health, University of Virginia, Charlottesville, VA 22908, USA
    Dev Biol 319:201-10. 2008
    ..Coupled with the infertility due to haploinsufficiency noted in chimeric mice with deletion of Tssk1 and 2 (companion paper) this centriolar kinase/substrate pair is predicted to play an indispensable role during spermiogenesis...
  8. pmc Phosphorylation of mouse sperm axoneme central apparatus protein SPAG16L by a testis-specific kinase, TSSK2
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Biol Reprod 79:75-83. 2008
    ..SPAG16L can be phosphorylated by TSSK2 in vitro. Finally, TSSK2 is absent or markedly reduced from the testes in most of the SPAG16L-null mice. These data support the conclusion that SPAG16L is a TSSK2 substrate...
  9. ncbi A heterozygous mutation disrupting the SPAG16 gene results in biochemical instability of central apparatus components of the human sperm axoneme
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Biol Reprod 77:864-71. 2007
    ....
  10. ncbi Accelerated mortality from hydrocephalus and pneumonia in mice with a combined deficiency of SPAG6 and SPAG16L reveals a functional interrelationship between the two central apparatus proteins
    Zhibing Zhang
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Cell Motil Cytoskeleton 64:360-76. 2007
    ..The findings also demonstrate that SPAG6 and SPAG16L have related roles in controlling the function of cilia in the brain and lung...
  11. pmc Expression profile of male germ cell-associated genes in mouse embryonic stem cell cultures treated with all-trans retinoic acid and testosterone
    Celso Silva
    Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida, USA
    Mol Reprod Dev 76:11-21. 2009
    ..Furthermore, these data represent an important first step in designing a plausible directed differentiation protocol for male germ cells...
  12. pmc Functional deficiencies and a reduced response to calcium in the flagellum of mouse sperm lacking SPAG16L
    Kathleen A Lesich
    Department of Biological Sciences, Oakland University, Rochester, Michigan, USA
    Biol Reprod 82:736-44. 2010
    ..This deficit in motor function, and an increased rigidity of the midpiece region which we detected in the passive flagella, together can explain the observed motility characteristics of the Spag16L-null sperm...
  13. pmc Transcriptional regulation of an axonemal central apparatus gene, sperm-associated antigen 6, by a SRY-related high mobility group transcription factor, S-SOX5
    Elizabeth Anne Kiselak
    Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    J Biol Chem 285:30496-505. 2010
    ..The present study demonstrates that SPAG6 is a S-SOX5 target gene, indicating a key role for S-SOX5 in the formation and function of motile cilia...
  14. pmc Spag16, an axonemal central apparatus gene, encodes a male germ cell nuclear speckle protein that regulates SPAG16 mRNA expression
    David R Nagarkatti-Gude
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America
    PLoS ONE 6:e20625. 2011
    ..This is a unique example of a highly conserved axonemal protein gene that encodes two protein products with different functions...
  15. pmc MEIG1 is essential for spermiogenesis in mice
    Zhibing Zhang
    Departments of Obstetrics and Gynecology and Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
    Proc Natl Acad Sci U S A 106:17055-60. 2009
    ..Our findings reveal a critical role for the MEIG1/PARCG partnership in manchette structure and function and the control of spermiogenesis...