The BTG4 and CAF1 complex prevents the spontaneous activation of eggs by deadenylating maternal mRNAs.
Once every menstrual cycle, eggs are ovulated into the oviduct where they await fertilization. The ovulated eggs are arrested in metaphase of the second meiotic division, and only complete meiosis upon fertilization. It is crucial that the maintenance of metaphase arrest is tightly controlled, because the spontaneous activation of the egg would preclude the development of a viable embryo (Zhang et al. 2015 J. Genet. Genomics 42, 477-485. (doi:10.1016/j.jgg.2015.07.004); Combelles et al. 2011 Hum. Reprod. 26, 545-552. (doi:10.1093/humrep/deq363); Escrich et al. 2011 J. Assist. Reprod. Genet. 28, 111-117. (doi:10.1007/s10815-010-9493-5)). However, the mechanisms that control the meiotic arrest in mammalian eggs are only poorly understood. Here, we report that a complex of BTG4 and CAF1 safeguards metaphase II arrest in mammalian eggs by deadenylating maternal mRNAs. As a follow-up of our recent high content RNAi screen for meiotic genes (Pfender et al. 2015 Nature 524, 239-242. (doi:10.1038/nature14568)), we identified Btg4 as an essential regulator of metaphase II arrest. Btg4-depleted eggs progress into anaphase II spontaneously before fertilization. BTG4 prevents the progression into anaphase by ensuring that the anaphase-promoting complex/cyclosome (APC/C) is completely inhibited during the arrest. The inhibition of the APC/C relies on EMI2 (Tang et al. 2010 Mol. Biol. Cell 21, 2589-2597. (doi:10.1091/mbc.E09-08-0708); Ohe et al. 2010 Mol. Biol. Cell 21, 905-913. (doi:10.1091/mbc.E09-11-0974)), whose expression is perturbed in the absence of BTG4. BTG4 controls protein expression during metaphase II arrest by forming a complex with the CAF1 deadenylase and we hypothesize that this complex is recruited to the mRNA via interactions between BTG4 and poly(A)-binding proteins. The BTG4-CAF1 complex drives the shortening of the poly(A) tails of a large number of transcripts at the MI-MII transition, and this wave of deadenylation is essential for the arrest in metaphase II. These findings establish a BTG4-dependent pathway for controlling poly(A) tail length during meiosis and identify an unexpected role for mRNA deadenylation in preventing the spontaneous activation of eggs.
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Michał
0000-0001-5407-4273
M
Pasternak
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Sybille
S
Pfender
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Balaji
B
Santhanam
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany melina.schuh@mpibpc.mpg.de.
Melina
0000-0003-0025-8952
M
Schuh
D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005095:Exoribonucleases / Q000378:metabolism; D005260:Female; D005306:Fertilization; D008540:Meiosis; D008677:Metaphase; D051379:Mice; D009865:Oocytes / Q000502:physiology*; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D023121:RNA, Messenger, Stored / Q000378:metabolism*; D012097:Repressor Proteins; D012260:Ribonucleases
D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins; D005095:Exoribonucleases; D011506:Proteins; D023121:RNA, Messenger, Stored; D012097:Repressor Proteins; D012260:Ribonucleases; C485928:Btg4 protein, mouse; C489778:Cnot7 protein, mouse
cell cycle; deadenylation; meiosis; oocyte