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SERINE/THREONINE PHOSPHATASES: ROLE IN SPERMATOGENESIS AND SPERM FUNCTION

Dudiki, Tejasvi

Abstract Details

2014, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
In mammals, sperm attain motility and the ability to fertilize eggs during their passage through the epididymis. Changes in motility characteristics, called hyperactivation, occur in the female reproductive tract. Serine/threonine protein phosphorylation controlled by protein kinases and protein phosphatases has been identified as an important mechanism involved in sperm maturation and function including motility. This study focuses on the serine/threonine phosphatases present in mammalian spermatozoa, PP2A and PP1γ2. The first part of this study confirms the presence of PP2A in sperm and shows that it undergoes marked changes in methylation (Leu 309), tyrosine phosphorylation (Tyr 307) and catalytic activity during epididymal sperm maturation. Catalytic activity of PP2A declined as PP2A was demethylated during epididymal sperm maturation. Further, inhibition/demethylation of PP2A in caudal sperm resulted in increased phosphorylation of glycogen synthase kinase-3 and sperm motility parameters resembling hyperactivation. The results show for the first time that changes in PP2A activity due to methylation and tyrosine phosphorylation occur in sperm and that these changes may play an important role in the regulation of sperm function. The second part of the study focuses on unraveling the significance of the testis specific PP1γ2 in spermatogenesis and sperm function. PP1γ1 and PP1γ2 are alternately spliced transcripts of the same gene Ppp1cc and are identical except at their extreme C-termini. While PP1γ1 is ubiquitous in somatic cells, PP1γ2 is expressed exclusively in male germ cells. Ppp1cc knockout male mice (-/-) are sterile due to severely impaired sperm morphogenesis. Fertility can be restored in Ppp1cc -/- mice by high levels of transgenic PP1γ2 expression in germ cells of testis. Similarly, we wanted to determine if PP1γ1 is capable of restoring sperm morphogenesis and sperm function in Ppp1cc -/- mice. We generated four different transgenic Rescue mice lines. The first three transgenic lines were generated using cDNA of PP1γ1 mRNA including the initial sequence or entire intron 7. Lack of fertility in these three lines was attributed to low levels of transgenic PP1γ1 in testis probably due to instability of the PP1γ1 mRNA containing intron 7 in testis. Testis expression of PP1γ1 occurred at significant levels only when the transgene lacked the intron7. Levels of the PP1γ1 transgene in this line (Rescue IV) were comparable to PP1γ2 levels in Ppp1cc +/- mice testes. Sperm morphogenesis was restored with the PP1γ1 transgene in Ppp1cc -/- mice but small percentage of these males remained infertile due to altered sperm motility. The results of this study suggest that despite the ability of PP1γ1 to support sperm morphogenesis, it is detrimental for male fertility and hence excluded in differentiating spermatogenic cells by alternate splicing and miRNA mediated instability of its transcript.
Srinivasan Vijayaraghavan, PhD (Committee Chair)
Kline Douglas, PhD (Committee Member)
Wen-Hai Chou, PhD (Committee Member)
Gary Koski, PhD (Committee Member)
Andrea Case, PhD (Committee Member)
206 p.

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Citations

  • Dudiki, T. (2014). SERINE/THREONINE PHOSPHATASES: ROLE IN SPERMATOGENESIS AND SPERM FUNCTION [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1416354965

    APA Style (7th edition)

  • Dudiki, Tejasvi. SERINE/THREONINE PHOSPHATASES: ROLE IN SPERMATOGENESIS AND SPERM FUNCTION. 2014. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1416354965.

    MLA Style (8th edition)

  • Dudiki, Tejasvi. "SERINE/THREONINE PHOSPHATASES: ROLE IN SPERMATOGENESIS AND SPERM FUNCTION." Doctoral dissertation, Kent State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1416354965

    Chicago Manual of Style (17th edition)