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The Functions and Regulation of mRNA Processing During Male Germ Cell Development

Hannigan, Molly M
http://rave.ohiolink.edu/etdc/view?acc_num=case1554291304563947

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Alternative RNA processing is a critical factor in increasing transcriptome complexity during cell differentiation and tissue development. Remarkably, spermatogenic cells express more alternatively processed transcripts compared to most whole tissues. While alternative mRNA processing is known to be prevalent in the testis, the full extent of its regulation and biological impact remain unclear. Here, we describe distinct stage-specific programs of pre-mRNA alternative splicing in male germ cells, revealing that the greatest number of splicing changes occur between mitosis and meiosis. Further, we identify an essential function for the RNA binding protein, Ptbp2, in regulating stage-specific alternative splicing. Using high-throughput sequencing technologies, we demonstrate that Ptbp2 regulates the alternative splicing of over 200 genes and inhibits splicing of alternative exons by directly binding near 3’ splice sites. Strikingly, Ptbp2 regulates the alternative splicing of a network of genes important for germ-Sertoli cell communication, protein transport, and mitochondria dynamics. Indeed, using ultrastructural approaches, we observed cellular protein trafficking defects and increased mitochondria fission in the absence of Ptbp2. Using polyA-seq, we revealed stage-specific regulation of alternative polyadenylation during male germ cell development. In contrast to the regulation of alternative splicing during spermatogenesis, the majority of differences in 3’-end formation occur in post-meiotic germ cells and are accompanied by significant 3’UTR shortening. Collectively, the data reveal that alternative pre-mRNA processing is highly regulated during spermatogenesis and offers important insights into the physiological functions of alternative splicing in the mammalian germline. 
Donny Licatalosi (Advisor)
203 p.
Biochemistry; Molecular Biology
RNA processing; Alternative Splicing; RNA binding proteins; PTBP2; Spermatogenesis

Recommended Citations

Citations

  • Hannigan, M. M. (2019). The Functions and Regulation of mRNA Processing During Male Germ Cell Development [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1554291304563947

    APA Style (7th edition)

  • Hannigan, Molly. The Functions and Regulation of mRNA Processing During Male Germ Cell Development. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1554291304563947.

    MLA Style (8th edition)

  • Hannigan, Molly. "The Functions and Regulation of mRNA Processing During Male Germ Cell Development." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554291304563947

    Chicago Manual of Style (17th edition)

case1554291304563947
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© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.