Embryonic Poly-A-Binding Protein (Epab) Is Necessary for Mammalian Oogenesis.

Abstract

In most metazoa, oocytes become arrested at the prophase of the first meiotic division. This arrest may last a few years in Xenopus and several decades in humans, and is characterized by synthesis and storage of dormant mRNA. The resumption of meiosis marks the onset of oocyte maturation and is associated with suppression of transcription, which persists until embryonic genome activation. Consequently, gene expression during oocyte maturation, fertilization and early embryogenesis depends on translational activation of maternally-derived mRNAs stored in the oocyte during the first meiotic arrest. Embryonic poly(A) binding protein (ePAB), identified in Xenopus oocytes, is the predominant poly(A) binding protein during early Xenopus development until zygotic genome activation (ZGA). In Xenopus oocytes, ePAB stabilizes maternal mRNAs and promotes their translation, and therefore seems to play a central role in the translational regulation of maternally derived transcripts during a critical period of early development when transcription is suppressed. Mouse and human Epab's have been identified and demonstrate an expression pattern similar to that of Xenopus ePAB. We hypothesized that Epab plays a key role in mammalian early development. To test our hypothesis, we generated Epab-null mice by targeted deletion of Epab exon 2 which resulted in a translational frame shift and generated a premature stop codon. Male and female ePAB -/- mice were viable and appeared phenotypically normal. However, ePAB-/- female mice were infertile, while ePAB-/- males and ePAB+/- of both sexes demonstrated normal fertility. Superovulation and mating with wild type males showed that ePAB-/- female mice could not generate embryos. In addition, ePAB-/- females exhibited a marked reduction in the number of Graafian follicules in their ovaries, and produced a significantly decreased number of oocytes with impaired maturation in response to superovulation. Here, we report that Epab-null phenotype is associated with infertility and impaired oocyte maturation. Our findings indicate that Epab is necessary for oogenesis and reproduction in mammals. Molecular mechanisms of Epab-mediated translational activation during mammalian early development, and their implications for human reproduction remain to be elucidated. This research was supported by NIH HD046581-01 (ES). (platform)