Early embryonic developmental processes are regulated through the translation of maternal mRNAs prior to the onset of zygotic transcription. In many organisms, including Drosophila, Xenopus and the mouse, mRNA translation is regulated through the control of maternal mRNA poly[A] tail length. This process, termed cytoplasmic polyadenylation, is directed through a cis-acting uracil rich mRNA sequence termed the cytoplasmic polyadenylation element (CPE) and a cytoplasmic polyadenylation element binding protein (CPEB). Despite the recent advances in our knowledge concerning the importance of cytoplasmic polyadenylation in regulating early developmental processes in model organisms, it is not known if this process controls mRNA translation during human oocyte maturation. Recent studies in my laboratory have identified a human cDNA which shares extensive homology to both Xenopus and mouse CPEB sequences. We have evidence that the human CPEB mRNA is alternatively spliced and encodes CPEB proteins with different N-terminal extensions. Alternative splicing of CPEB mRNAs has not been previously reported. The mRNA encoding human CPEB is expressed at high levels in ovarian tissue, consistent with a possible role in regulating oocyte maturation. The studies proposed in this application are designed to test the hypothesis that the putative human CPEB encodes a bona fide CPE-binding protein which mediates cytoplasmic polyadenylation. We will characterize the functional role of the alternately spliced variants of the human CPEB mRNA which we have identified. This study will also identify human maternal mRNAs which encode candidate CPE sequences in their 3' untranslated regions. We will determine if translation of these mRNAs is subject to cytoplasmic polyadenylation-mediated control in a heterologous Xenopus assay system and during human oocyte maturation. Successful resolution of this study would establish a role for CPEB in human development and further our understanding of translational control through CPEB-mediated cytoplasmic polyadenylation in both human and model systems.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD038081-01A1
Application #
6202832
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Tasca, Richard J
Project Start
2000-08-01
Project End
2001-04-30
Budget Start
2000-08-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$74,859
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Jensen, Liselotte E; Barbaux, Sandrine; Hoess, Katy et al. (2004) The human T locus and spina bifida risk. Hum Genet 115:475-82
Welk, J F; Charlesworth, A; Smith, G D et al. (2001) Identification and characterization of the gene encoding human cytoplasmic polyadenylation element binding protein. Gene 263:113-20