Characterizing Mammalian Embryonic polyA Binding Protein

Summary

Principal Investigator: E Seli
Abstract: This application for the Mentored Clinical Scientist Development Award is submitted so as to enable the candidate to gain necessary didactic and scientific training in developmental biology and molecular genetics, and to enable him to develop a career in academic reproductive endocrinology with a focus on molecular biology of oocyte and early embryo development as well as associated reproductive disorders. Elucidation of molecular mechanisms regulating gene expression during gametogenesis and early embryogenesis may have important implications for the understanding and treatment of reproductive problems such as oocyte aging, aneuploidy, and embryo loss. In this application, the candidate proposes to investigate a mammalian polyA binding protein (PABP) and its role in the regulation of gene expression during oocyte and early embryo development. Oocyte maturation is associated with suppression of transcription. Gene expression in mature oocyte and early embryo until the activation of zygotic transcription is regulated by translational activation and repression of maternally derived mRNAs. The first step in translational activation of stored maternal mRNAs is cytoplasmic extension of the polyA tail. A subsequent step is dissociation of the maskin-elF4E complex, so that the translationally essential elF4E-elF4G complex can form. Both of these processes have been intensively studied in the Xenopus oocyte. There, unmasking requires both cytoplasmic polyadenylation and a PABP. Although a cytoplasmic PABP (PABP1) has long been known, it is not expressed in oocytes and early embryos. The candidate has recently identified an oocyte and embryo-specific PABP in Xenopus named ePAB. As the predominant PABP during Xenopus early development and an inhibitor of deadenylation, ePAB most likely regulates polyA tail length and unmasking/translation of maternal mRNAs. Based on similarities between Xenopus and mouse in the molecular mechanisms regulating the control of cytoplasmic polyadenylation, the candidate hypothesized that a mammalian ePAB exists, and he identified a putative mouse ePAB ortholog. In this application, he aims to confirm the initial findings by determining its time- and tissue-specific expression pattern, and to further characterize its function in cytoplasmic polyadenylation, specifically in processivity and tail length control. Subsequently, the candidate will create an ePAB knock-out mouse. This application for the mentored grant K08 award is submitted so as to enable the candidate to gain necessary didactic and scientific training in developmental biology and molecular genetics, and to enable him to develop a career in academic Reproductive Endocrinology with a focus on molecular biology of oocyte and early embryo development and associated reproductive disorders.
Funding Period: 2004-09-22 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. pmc Alternative splicing of the mouse embryonic poly(A) binding protein (Epab) mRNA is regulated by an exonic splicing enhancer: a model for post-transcriptional control of gene expression in the oocyte
    Emre Seli
    Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, 300 George Street, Suite 770J, New Haven, CT 06511, USA
    Mol Hum Reprod 14:393-8. 2008
  2. pmc The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium
    Fethiye Sinem Karipcin
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA
    Reprod Sci 18:145-55. 2011
  3. pmc Embryonic poly(A)-binding protein (ePAB) phosphorylation is required for Xenopus oocyte maturation
    Kyle Friend
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, LSOG 304D, New Haven, CT 06520, USA
    Biochem J 445:93-100. 2012
  4. pmc Epab and Pabpc1 are differentially expressed during male germ cell development
    Saffet Ozturk
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Reprod Sci 19:911-22. 2012
  5. pmc Embryonic poly(A)-binding protein (EPAB) is required for oocyte maturation and female fertility in mice
    Ozlem Guzeloglu-Kayisli
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, LSOG 304D, New Haven, CT 06520, USA
    Biochem J 446:47-58. 2012

Detail Information

Publications6

  1. pmc Alternative splicing of the mouse embryonic poly(A) binding protein (Epab) mRNA is regulated by an exonic splicing enhancer: a model for post-transcriptional control of gene expression in the oocyte
    Emre Seli
    Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, 300 George Street, Suite 770J, New Haven, CT 06511, USA
    Mol Hum Reprod 14:393-8. 2008
    ..Our findings suggest that SNPs may alter the ratio between alternative splicing variants of oocyte-specific proteins. The role that these subtle differences play in determining individual reproductive outcome remains to be determined...
  2. pmc The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium
    Fethiye Sinem Karipcin
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA
    Reprod Sci 18:145-55. 2011
    ..In ectopic endometrium, elevated cytokine levels associated with endometriosis likely reduce HuR expression...
  3. pmc Embryonic poly(A)-binding protein (ePAB) phosphorylation is required for Xenopus oocyte maturation
    Kyle Friend
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, LSOG 304D, New Haven, CT 06520, USA
    Biochem J 445:93-100. 2012
    ..Our results provide the first insight into the role of post-translational modifications in regulating PABP protein activity in vivo...
  4. pmc Epab and Pabpc1 are differentially expressed during male germ cell development
    Saffet Ozturk
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Reprod Sci 19:911-22. 2012
    ....
  5. pmc Embryonic poly(A)-binding protein (EPAB) is required for oocyte maturation and female fertility in mice
    Ozlem Guzeloglu-Kayisli
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, LSOG 304D, New Haven, CT 06520, USA
    Biochem J 446:47-58. 2012
    ..The findings from the present study indicate that EPAB is necessary for oogenesis, folliculogenesis and female fertility in mice...