Do we need Y chromosome for successful reproduction?
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
- Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packagingJonathan 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....
- Mouse zygotes respond to severe sperm DNA damage by delaying paternal DNA replication and embryonic developmentJoanna 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...
- Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouseYasuhiro 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. ..
- SSTY proteins co-localize with the post-meiotic sex chromatin and interact with regulators of its expressionAurélie 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...
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