Do we need Y chromosome for successful reproduction?

Summary

Principal Investigator: Monika A Ward
Abstract: DESCRIPTION (provided by applicant): Male infertility affects 5-10% of the population. A major factor associated with male infertility is Y chromosome deletions, yet our understanding of the requirement for specific genes on the Y chromosome and of their roles in sperm production/function is still poor. Y chromosome genes may provide essential spermatogenic functions or just potentiate the spermatogenic process. Our long-term goal is to define the function of Y chromosome encoded genes in mice in a context of assisted reproduction technologies (ART) as a way to model human Y- linked infertility cases. We have established that only two Y chromosome genes, testis determinant gene Sry and spermatogonial proliferation factor Eif2s3y are required for production of male gametes capable of participating in assisted fertilization. In Preliminary Data we show that males with a Y complement limited to Sry and Eif2s3y have spermatogenesis arrest and do not produce mature sperm. The precursor haploid germ cells (spermatids) are rare and often abnormal. Nevertheless, with round spermatid injection (ROSI) we succeeded in producing viable, healthy, and fertile progeny. This offers a promise to men with extensive Y gene loss and resulting azoospermia. Here, our specific goal is to define whether ART can be achieved even without this minimum Y gene contribution. We will test the hypothesis that the Y chromosome complement can be eliminated entirely while retaining production of functional male gametes. In Aim 1 we wil test if transgenic activation of Sox9, a downstream effector of Sry, will effectively replace Sry function and whether Sry-to-Sox9 replacement affects spermatogenesis and fertility, testing directly for the as yet unknown function of these genes in mature gonads. We will also establish if Eif2s3x, an X encoded homologue of Eif2s3y, can replace Eif2s3y function in spermatogonial proliferation. We will generate and characterize mice transgenic for Eif2s3x, and assess whether overexpression of Eif2s3x can rescue spermatogonial proliferation arrest in XOSry mice. In Aim 2, we will produce males without any Y genes but with overexpression of Eif2s3x and with transgenic activation of Sox9, as well as males with one Y gene retained and the other replaced. We will investigate how the presence of these genes affects spermatogenesis progression. We will also test if spermatogenesis in these males enables development of germ cells functional in ART, and whether such produced offspring are normal. In Aim 3, we will attempt to rescue spermatogonial arrest in testes of mature males with in vivo Eif2s3y gene transfer using novel 'active transgenesis'approach and ultrasound mediated gene delivery. Our studies will advance the understanding of (1) the roles that key players of sex determination (Sry and Sox9) play in mature gonads;(2) the roles of sex chromosome genes (Eif2s3y and Eif2s3x) in the initiation of spermatogenesis;and (3) the compatibility of extensive Y gene loss with successful ART. Our results should translate to enhance treatment of human infertility associated with Y chromosome deletions. !
Funding Period: 2012-08-25 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. pmc Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packaging
    Jonathan M Riel
    Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii, Honolulu HI 96822, USA
    J Cell Sci 126:803-13. 2013
  2. pmc Mouse zygotes respond to severe sperm DNA damage by delaying paternal DNA replication and embryonic development
    Joanna E Gawecka
    Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, University of Hawaii at Manoa, John A Burns School of Medicine, Honolulu, Hawaii, United States of America
    PLoS ONE 8:e56385. 2013
  3. pmc Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse
    Yasuhiro Yamauchi
    Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii, 1960 East West Road, Honolulu, HI 96822, USA
    Science 343:69-72. 2014
  4. pmc SSTY proteins co-localize with the post-meiotic sex chromatin and interact with regulators of its expression
    Aurélie Comptour
    Institut National de la Santé et de la Recherche Médicale INSERM U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique, UMR8104, Paris, France Faculté de Médecine, Universite Paris Descartes, Paris, France
    FEBS J 281:1571-84. 2014

Detail Information

Publications4

  1. pmc Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packaging
    Jonathan M Riel
    Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii, Honolulu HI 96822, USA
    J Cell Sci 126:803-13. 2013
    ....
  2. pmc Mouse zygotes respond to severe sperm DNA damage by delaying paternal DNA replication and embryonic development
    Joanna E Gawecka
    Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, University of Hawaii at Manoa, John A Burns School of Medicine, Honolulu, Hawaii, United States of America
    PLoS ONE 8:e56385. 2013
    ..Our data demonstrate that the zygote responds to sperm DNA damage through a non-apoptotic mechanism that acts by slowing paternal DNA replication and ultimately leads to arrest in embryonic development...
  3. pmc Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse
    Yasuhiro Yamauchi
    Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii, 1960 East West Road, Honolulu, HI 96822, USA
    Science 343:69-72. 2014
    ..Our findings are relevant, but not directly translatable, to human male infertility cases. ..
  4. pmc SSTY proteins co-localize with the post-meiotic sex chromatin and interact with regulators of its expression
    Aurélie Comptour
    Institut National de la Santé et de la Recherche Médicale INSERM U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique, UMR8104, Paris, France Faculté de Médecine, Universite Paris Descartes, Paris, France
    FEBS J 281:1571-84. 2014
    ..As Slx/Slxl1 and Sly genes have been shown to be involved in the XY intra-genomic conflict, which affects the offspring sex ratio, Ssty may constitute another player in this conflict...

Research Grants31

  1. DMRT1 IN MAMMALIAN SEXUAL DEVELOPMENT
    David A Zarkower; Fiscal Year: 2013
    ..The results of this study should aid in treatment of gonadal cancer and infertility, and will inform studies of cell fate reprogramming and design of novel male contraceptives. ..
  2. Regulation of chromosome synapsis in mice
    Peijing Jeremy Wang; Fiscal Year: 2013
    ..Completion of this project will provide insight into the etiology of male infertility and birth defects in humans. ..
  3. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  4. Sexual Development of the Drosophila Germline
    MARK B VAN DOREN; Fiscal Year: 2013
    ..This model can be used as a framework for continued studies of germline sex determination in Drosophila and other animal species, including humans. ..
  5. DNA Damage Response Pathways in Meiotic Sex Chromosome Inactivation
    Satoshi Namekawa; Fiscal Year: 2013
    ..The proposed study in germ cells will potentially reveal a link between DDR pathways and epigenetic programming that can be generalized to somatic cells. ..
  6. Lineage tracing of germline stem cell differentiation in adult ovaries
    Ning Wang; Fiscal Year: 2013
    ....
  7. Sex chromosome control of chromatin in the gametes
    BLUMA JESSICA LESCH; Fiscal Year: 2013
    ..Fulfillment of each of these aims will enhance our current understanding of sex-specific gamete development, and improve clinical approaches to disorders of fertility and early embryonic development. ..
  8. Genetic Basis of Oligozoospermia in Infertile Males
    Alexander N Yatsenko; Fiscal Year: 2013
    ..The long-term career goals of the applicant is to become an independent physician-scientist focused on studying genetic disorders that affect male reproductive system. ..
  9. Human Exposure to Bisphenol A, Phthalates and Fertility, Pregnancy Outcomes
    Russ B Hauser; Fiscal Year: 2013
    ..abstract_text> ..
  10. Genomic Studies Mammalian Y Chromosomes
    David C Page; Fiscal Year: 2013
    ..We anticipate that the sequence of the W chromosome will inform our understanding of human biology by offering insights into female fertility, oogenesis, and sex determination. ..
  11. MRNA PROCESSING IN REPRODUCTION AND FERTILIZATION
    Clinton C MacDonald; Fiscal Year: 2013
    ..Using a variety of techniques, we want to learn the molecular causes of why sperm production fails in males missing the CSTF2T gene, to better understand how to assist these infertile couples. ..
  12. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  13. AMERICAN SOCIETY OF ANDROLOGY ANNUAL MEETING
    DONNA LEE VOGEL; Fiscal Year: 2013
    ..abstract_text> ..
  14. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
    ..abstract_text> ..
  15. Functional Analysis of the Embryonic Epigenome in a Non-rodent Model
    Mark E Westhusin; Fiscal Year: 2013
    ....
  16. Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
    Tracie R Baker; Fiscal Year: 2013
    ..The University of Wisconsin has numerous NIH-sponsored training programs, core facilities and funded researchers making it an ideal training environment for me to develop as an independent scientist. ..
  17. The MRAD9 Radioresistance Gene
    Howard B Lieberman; Fiscal Year: 2013
    ..abstract_text> ..
  18. PTIP as an epigenetic regulator in male meiosis
    Guo Zhang Zhu; Fiscal Year: 2013
    ..Furthermore, collected information may offer insights into unexplained (or idiopathic) infertility in men and may lead to new strategies for male contraception and assisted reproduction. ..
  19. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  20. Penn Center for Study of Epigenetics in Reproduction
    Marisa S Bartolomei; Fiscal Year: 2013
    ..abstract_text> ..
  21. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
  22. Regulation of Spermatogenesis by X-linked miRNAs
    Wei Yan; Fiscal Year: 2013
    ..Data from the present study will contribute insight into the function of X-linked miRNAs in the control of sperm production and male fertility. ..