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BTG4 is a meiotic cell cycle–coupled maternal-zygotic-transition licensing factor in oocytes

Nature Structural & Molecular Biology volume 23, pages 387–394 (2016)Cite this article

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Abstract

The mRNAs stored in oocytes undergo general decay during the maternal-zygotic transition (MZT), and their stability is tightly interconnected with meiotic cell-cycle progression. However, the factors that trigger decay of maternal mRNA and couple this event to oocyte meiotic maturation remain elusive. Here, we identified B-cell translocation gene-4 (BTG4) as an MZT licensing factor in mice. BTG4 bridged CNOT7, a catalytic subunit of the CCR4–NOT deadenylase, to eIF4E, a key translation initiation factor, and facilitated decay of maternal mRNA. Btg4-null females produced morphologically normal oocytes but were infertile, owing to early developmental arrest. The intrinsic MAP kinase cascade in oocytes triggered translation of Btg4 mRNA stored in fully grown oocytes by targeting the 3′ untranslated region, thereby coupling CCR4–NOT deadenylase–mediated decay of maternal mRNA with oocyte maturation and fertilization. This is a key step in oocyte cytoplasmic maturation that determines the developmental potential of mammalian embryos.

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Figure 1: Btg4 is a maternal-effect gene essential for MZT.
Figure 2: BTG4 is required for decay of maternal mRNA.
Figure 3: BTG4 interacts with CCR4–NOT transcription-complex subunits CNOT7 and CNOT8 and is required for 3′-poly(A)-tail shortening of maternal transcripts.
Figure 4: Interaction with CNOT7 and CNOT8 is essential for BTG4 function in vivo.
Figure 5: BTG4 is an adaptor protein that mediates the interaction between CNOT7 and eIF4E.
Figure 6: Btg4-mRNA translation is coupled to the meiotic cell cycle by its 3′ UTR.
Figure 7: ERK1/2 triggers Btg4-mRNA translation by targeting its 3′ UTR.
Figure 8: Summary of BTG4 function and regulation during MZT.

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Acknowledgements

This study was funded by the National Basic Research Program of China (2012CB944403) and the National Natural Science Foundation of China (31528016, 91519313, and 31371449) to H.-Y.F. We thank B. Zhang (Peking University) for vectors.

Author information

Author notes

  1. Chao Yu, Shu-Yan Ji, Qian-Qian Sha, Yujiao Dang, Jian-Jie Zhou and Yin-Li Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China

    Chao Yu, Shu-Yan Ji, Qian-Qian Sha, Jian-Jie Zhou, Yin-Li Zhang, Yang Liu & Heng-Yu Fan

  2. Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing, China

    Yujiao Dang, Boqiang Hu & Fuchou Tang

  3. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Zhong-Wei Wang & Qing-Yuan Sun

  4. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

    Shao-Chen Sun

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  1. Chao Yu
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Contributions

H.-Y.F. and C.Y. conceived the project. H.-Y.F., C.Y., S.-Y.J., Q.-Q.S., Y.D., Y.-L.Z., and F.T. designed and analyzed experiments. C.Y., S.-Y.J., Q.-Q.S., Y.D., Y.-L.Z., J.-J.Z., Y.L., B.H., and S.-C.S. performed experiments. Z.-W.W. and Q.-Y.S. assisted in microinjection of mouse embryos. C.Y., Y.-L.Z., and H.-Y.F. wrote the paper. C.Y., S.-Y.J., Q.-Q.S., Y.D., J.-J.Z., and Y.-L.Z. contributed equally to this work.

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Correspondence to Heng-Yu Fan.

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Integrated supplementary information

Supplementary Figure 1 Phenotypic analyses of Btg4-knockout mice.

(a) Quantitative RT-PCR results showing relative expression levels of mouse Btg4 in somatic tissues, oocytes (GV and MII), and early embryos (1-cell, 2-cell, 4-cell and blastula). Error bars indicate S.E.M. (b) PCR results of tail genomic DNAs. The WT allele (“+”) was amplified with WT-F and WT-R primers, and a 7-nucleotide-deleted null allele (“−”) was amplified with the primer pairs GT-F and GT-R. “+/–” and “−/−” refer to mice heterozygous and homozygous for the Btg4 mutant allele, respectively. (c) Average body weights of 3-week-old WT, Btg4+/−, and Btg4−/− females. n=9 for each genotype. Error bars indicate S.E.M. (d) Ovarian histology of WT and Btg4−/− females (3-week and 18-week old). Scale bar: 200 μm. (e) The average numbers of ovulated oocytes by 3-week-old WT (n=4) and Btg4−/− (n=5) females, as determined by a superovulation assay. Error bars indicate S.E.M. (f) Average in vitro GVBD and PB1 emission (PBE) rates of GV oocytes collected from WT and Btg4−/− females. The numbers of WT and Btg4−/− oocytes analyzed were 87 and 105, respectively. Error bars indicate S.E.M. (g) Representative images of early embryos collected from the oviducts of WT, Btg4−/− and Btg4 C-terminal truncated (Btg4ΔC/ΔC) females. n = 5 mice for each genotype at different developmental stages. Scale bar: 100 μm. (h) Pups born from Btg4−/− and WT foster mothers after embryo transfer. The genotypes of foster mothers and transferred embryos are indicated. (i) Genotyping results showing that the pups born by Btg4−/− foster mothers are Btg4 wild types.

Supplementary Figure 2 Immunofluorescence staining for markers of DNA damage and genome reprogramming in embryos derived from WT and Btg4−/− females.

(a) Immunofluorescent staining for DNA damage marker (γH2AX) in embryos derived from WT and Btg4−/− females. Scale bar; 10 μm. (b) BrdU incorporation assay showing DNA replication in zygotes derived from WT and Btg4−/− females mated with WT males. More than 20 embryos were analyzed for each genotype with different markers. Scale bar: 10 μm. (c) Immunofluorescent staining of 5‑methylcytosine (5mC) and 5‑hydroxymethylcytosine (5hmC) in zygotes derived from WT and Btg4−/− females mated with WT males. Scale bar: 10 μm. (d,e) Immunofluorescent staining of trimethylated histone H3 at lysine-4 (H3K4me3) (d) and lysine-9 (H3K9me3) (e) in zygotes derived from WT and Btg4−/− females mated with WT males. Scale bar: 10 μm.

Supplementary Figure 3 Immunofluorescence staining of genome transcriptional-activation markers in embryos derived from WT and Btg4−/− females.

(a) Immunofluorescent staining of phosphorylated RNA polymerase II CTD repeat YSPTSPS (pS2) in 1- or 2-cell embryos derived from WT and Btg4−/− females mated with WT males. Scale bar: 10 μm. (b-d) Immunofluorescent staining of acetylated histone H2B at lysine-5 (H2BK5-ace) (b), H3 at lysine-9 (H2BK9-ace) (c), and H3 at lysine-18 (H2BK18-ace) (d), in 1- or 2-cell embryos derived from WT and Btg4−/− females mated with WT males. Scale bar: 10 μm.

Supplementary Figure 4 Degradation of maternal mRNA during meiotic maturation and fertilization in WT and Btg4−/− oocytes.

(a) Numbers of gene transcripts detected by RNA-seq. (b) Down-regulated and up-regulated genes in WT and Btg4−/− oocytes/embryos at different stages. When comparing two samples, the up-regulation and down-regulation means the upper right one compared to the lower left one. (c) Heatmap illustration showing differentially expressed transcripts in WT oocytes/embryos. Cluster I, transcripts that are significantly degraded at GV to MII transition and not re-accumulate after that in WT oocytes. Cluster II, transcripts that are significantly degraded upon fertilization in WT oocytes. Cluster III, transcripts that are significantly up-regulated at zygote to 2-cell transition (or, zygotic genes). Cluster IV, transcripts that are significantly degraded at GV to MII transition but re-accumulated at zygote to 2-cell transition. (d) Heatmap illustration showing gene transcripts that are degraded during meiotic maturation in WT oocytes but failed to be degraded in Btg4−/− oocytes. (e) Heatmap illustration showing gene transcripts that are up-regulated during zygote to 2-cell transition in WT embryos but are not up-regulated in Btg4−/− 2-cell embryos.

Source data

Supplementary Figure 5 Btg4 knockout impairs zygotic genome activation.

(a) Overlapping results showing the numbers and percentages of genes up-regulated in Btg4-deleted oocytes at MII oocytes and zygotes. (b) Overlapping results showing the numbers and percentages of genes up-regulated and down-regulated in Btg4−/− at 2-cell stage when compared to WT 2-cell embryos. (c) RNA-seq results showing the relative expression levels of representative genes. The error bars indicate S.E.M. (d) qRT-PCR showing the relative levels of indicated transcripts in oocytes/zygotes of WT and Btg4−/− females. Error bars indicates S.E.M. (e) RNA-seq results showing the expression levels of Btg and Tob family genes in human oocytes and early embryos. FPKM numbers were extracted from previously published data1. (f) RNA-seq results showing mRNA expression levels of Btg/Tob family genes in mouse oocytes and early embryos. (g) RNA-seq results showing mRNA expression levels of Cnot7/8 in human oocytes and early embryos. FPKM numbers were extracted from previously published data. (h) Quantitative RT-PCR results showing the relative expression levels of mouse Cnot7/8 in somatic tissues, oocytes, and early embryos. Error bars indicate S.E.M.

Supplementary Figure 6 BTG proteins interact with eIF4E.

(a) Deadenylation assay demonstrating that BTG4 binding did not affect CNOT7 activity in vitro. (b) Co-IP results showing the interactions of BTG2, BTG3, and BTG4 with eIF4E. (c) Co-IP results showing the interactions of BTG2 and BTG3 mutant forms with eIF4E. (d-e) Co-IP results showing the interactions of eIF4E4 mutant forms with BTG4.

Supplementary Figure 7 Regulation of Btg4-mRNA translation by its 3′ UTR.

(a-b) Epifluorescence (a) and Western blot (b) results showing that injected mRNAs encoded for GFP-BTG4 were expressed in both GV and MII oocytes, but endogenous BTG4 was only detected in MII oocytes. Scale bar: 100 μm. (c) Fluorescent microscopy results showing meiotic maturation coupled activation of Btg4 3′-UTR. Scale bar: 100 μm. In vitro transcribed FLAG-GFP-(Btg4)3′-UTR mRNA and mCherry mRNA were co-injected into GV oocytes. The injected oocytes were then further cultured in M2 medium with or without milrinone for 12 h. (d) Polyadenylation enabled the expression of FLAG-GFP-(Btg4)3′-UTR mRNA in GV oocytes, even in the absence of CPE elements. Scale bar: 100 μm. In vitro transcribed WT and CPE-deleted FLAG-GFP-(Btg4)3′-UTR mRNAs were polyadenylated in vitro and injected into GV oocytes. The injected oocytes were than further cultured in M2 medium with or without milrinone for 12 h.

Supplementary Figure 8 Effects of Cpeb1 depletion and aurora A inhibition on mouse oocyte maturation.

(a) qRT-PCR results showing the knockdown efficiency of Cpeb1 in GV oocytes. Error bars indicate S.E.M. (b-c) Injection of Cpeb1 targeted siRNA (siCpeb1) impaired PB1 emission during in vitro mouse oocyte maturation. Error bars indicate S.E.M. Scale bar: 100 μm. (d) Injection of siCpeb1 impaired PB1 emission and disrupted chromosome alignment in the middle of the spindle. Scale bar: 10 μm. (e) MLN8273 did not block BTG4 expression and ERK1/2 phosphorylation in mature oocytes. (f-g) The aurora A inhibitor, MLN8273 blocked PB1 emission, and disrupted chromosome alignment in the middle of the spindle during in vitro mouse oocyte maturation. Scale bar: 10 μm. Error bars indicate S.E.M. (h) The morphology of MLN8237 treated oocytes showed that MLN8273 blocked PB1 emission during in vitro mouse oocyte maturation. Scale bar: 100 μm.

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Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 2–4 (PDF 8657 kb)

Supplementary Table 1

FPKM of RNA-seq results (XLS 8170 kb)

Supplementary Data Set 1

Original images of gels and blots used in this study (PDF 5498 kb)

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Yu, C., Ji, SY., Sha, QQ. et al. BTG4 is a meiotic cell cycle–coupled maternal-zygotic-transition licensing factor in oocytes. Nat Struct Mol Biol 23, 387–394 (2016). https://doi.org/10.1038/nsmb.3204

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