title: A deadenylation negative feedback mechanism governs meiotic metaphase arrest.
abstract: In vertebrate oocytes, meiotic progression is driven by the sequential translational activation of maternal messenger RNAs stored in the cytoplasm. This activation is mainly induced by the cytoplasmic elongation of their poly(A) tails, which is mediated by the cytoplasmic polyadenylation element (CPE) present in their 3' untranslated regions. In Xenopus oocytes, sequential phase-specific translation of CPE-regulated mRNAs is required to activate the maturation-promoting factor, which in turn mediates entry into the two consecutive meiotic metaphases (MI and MII). Here we report a genome-wide functional screening to identify previously unknown mRNAs cytoplasmically polyadenylated at meiotic phase transitions. A significant fraction of transcripts containing, in addition to CPEs, (A + U)-rich element (ARE) sequences (characteristic of mRNAs regulated by deadenylation) were identified. Among these is the mRNA encoding C3H-4, an ARE-binding protein that we find to accumulate in MI and the ablation of which induces meiotic arrest. Our results suggest that C3H-4 recruits the CCR4 deadenylase complex to ARE-containing mRNAs and this, in turn, causes shortening of poly(A) tails. We also show that the opposing activities of the CPEs and the AREs define the precise activation times of the mRNAs encoding the anaphase-promoting complex inhibitors Emi1 and Emi2 during distinct phases of the meiotic cycle. Taken together, our results show that an 'early' wave of cytoplasmic polyadenylation activates a negative feedback loop by activating the synthesis of C3H-4, which in turn would recruit the deadenylase complex to mRNAs containing both CPEs and AREs. This negative feedback loop is required to exit from metaphase into interkinesis and for meiotic progression.
authors.affiliation: Centre for Genomic Regulation (CRG), Pompeu Fabra University (UPF), C/Dr Aiguader 88, 08003, Barcelona, Spain.
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Belloc
authors.forename: Raúl
authors.initials: R
authors.lastname: Méndez
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D025461:Feedback, Physiological / Q000235:genetics*; D005260:Female; D016678:Genome / Q000235:genetics; D008540:Meiosis / Q000235:genetics; D008677:Metaphase; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D026723:Polyadenylation / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C490388:Cpeb1 protein, Xenopus; D044783:F-Box Proteins; C498166:FBXO43 protein, Xenopus; C429107:FBXO5 protein, Xenopus; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D029867:Xenopus Proteins; C492201:ZFP36L2.1 protein, Xenopus; D039221:mRNA Cleavage and Polyadenylation Factors