The Program of Maternal mRNA Translation During Mouse Oocyte Meiosis: Complex Interactions and Multiple Inputs Control Protein Synthesis

In most species studied, oocyte growth is associated with the accumulation of large amounts of mRNAs that are stable and not translated. Translation of these maternal mRNAs is activated during oocyte maturation and the early stages of embryo development. In some species, embryo development up to gastrulation depends exclusively on translation of these mRNAs accumulated during growth, in the absence of gene transcription. The mechanisms underlying this post-transcriptional program have been extensively studied in model organisms but it is unclear whether the same regulations function in mammalian oocytes. We have used a genome-wide strategy to investigate patterns of maternal mRNA translation in the fully grown mouse oocyte and found that approximately 1/3 of the maternal mRNAs are recruited to translating polysomes during oocyte progression through the cell cycle, and 1/3 are released from the polysomes and often degraded, while the rest are constitutively translated. By analyzing the properties of the co-regulated mRNAs we found that binding elements for the Deleted in Azoospermia Like (DAZL) protein are enriched in a subset of transcripts whose translation is activated during maturation. DAZL plays a pivotal role during primordial germ cell development but its function in fully grown oocytes was not investigated. Loss of function studies confirmed that DAZL protein plays a role in translation of these mRNAs and the function of this RNA binding protein (RBP) is indispensable for oocyte maturation and early embryo development. Using a candidate approach, we determined that DAZL is required to recruit ribosomes to these mRNAs, that binding of multiple DAZL protein molecules is necessary for translational activation, and that accumulation of DAZL protein is necessary for progression through the meiotic cell cycle. Thus, DAZL is a major regulator of translation in fully grown oocytes. DAZL is also required for the CPEB1-dependent translation of a subset of maternal mRNAs. CPEB1 is an RBP required for polyadenylation of mRNAs, and, in frog, it regulates the translational activation that is in turn necessary to reenter the cell cycle. However, CPEB1-dependent activation of translation in mouse oocytes requires prior MPF activation and occurs well after oocyte reentry into the cell cycle. Thus, although the same proteins are involved, their regulation differs in mouse and frog oocytes. Finally, we found that meiotic resumption is necessary for translational activation, but that these regulations are not exclusively oocyte cell autonomous. Inputs from somatic cells surrounding the oocyte contribute to activation of translation of a subset of mRNAs and this somatic cell-dependent component is necessary for the developmental competence of the oocyte. Thus, multiple mechanisms of translational control are active in mouse oocytes and are required for completion of meiosis and for generation of an egg able to sustain embryo development. (Supported by NIH RO1 GM097165, RO1 GM115241 and P50 HD055764)