Role of <i>Cnot6l</i> in maternal mRNA turnover

Horvat, Filip; Fulka, Helena; Jankele, Radek; Malı́k, Radek; Ma, Jun; Solcova, Katerina; Sedláček, Radislav; Vlahoviček, Kristian; Schultz, Richard M.; Svoboda, Petr

doi:10.26508/lsa.201800084

Cited by 40 publications

(55 citation statements)

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“…Consistent with our findings, a recent study that was published while this manuscript was in revision reported decreased female fertility of Cnot6l ‐null mice. The study showed that in oocytes and zygotes derived from Cnot6l −/− mice, the timely degradation of maternal mRNA is perturbed (Horvat et al , ). However, the oocyte maturation process of Cnot6l ‐null oocytes was not observed in this study.…”

Section: Discussionmentioning

confidence: 99%

CNOT 6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte

et al. 2018

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Meiotic resumption‐coupled degradation of maternal transcripts occurs during oocyte maturation in the absence of mRNA transcription. The CCR4–NOT complex has been identified as the main eukaryotic mRNA deadenylase. In vivo functional and mechanistic information regarding its multiple subunits remains insufficient. Cnot6l, one of four genes encoding CCR4–NOT catalytic subunits, is preferentially expressed in mouse oocytes. Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset of maternal mRNAs during oocyte maturation. Overtranslation of these undegraded mRNAs caused microtubule–chromosome organization defects, which led to activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase. Consequently, Cnot6l−/− female mice were severely subfertile. The function of CNOT6L in maturing oocytes is mediated by RNA‐binding protein ZFP36L2, not maternal‐to‐zygotic transition licensing factor BTG4, which interacts with catalytic subunits CNOT7 and CNOT8 of CCR4–NOT. Thus, recruitment of different adaptors by different catalytic subunits ensures stage‐specific degradation of maternal mRNAs by CCR4–NOT. This study provides the first direct genetic evidence that CCR4–NOT‐dependent and particularly CNOT6L‐dependent decay of selective maternal mRNAs is a prerequisite for meiotic maturation of oocytes.

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Section: Discussionmentioning

confidence: 99%

CNOT 6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte

et al. 2018

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“…Significant progress has recently been made in understanding the regulation of mRNA stability in mammalian oocytes and zygotes. CNOT6L, which is a catalytic subunit of CCR4-NOT deadenylase, and its associated zinc finger protein 36-like 2 (ZFP36L2) protein were found to be essential for mRNA decay that accompanies oocyte meiotic maturation 6 – 8 . The B-cell translocation gene-4 (BTG4), which is an oocyte-specific adapter protein of CCR4-NOT, was identified as an MZT-licensing factor in mice that mediated mRNA clearance prior to ZGA 9 – 11 .…”

Section: Introductionmentioning

confidence: 99%

Dynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans

et al. 2020

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Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT). However, the dynamics, functional importance, and pathological relevance of maternal mRNA decay in human preimplantation embryos have not yet been analyzed. Here we report the zygotic genome activation (ZGA)-dependent and -independent maternal mRNA clearance processes during human MZT and demonstrate that subgroups of human maternal transcripts are sequentially removed by maternal (M)- and zygotic (Z)-decay pathways before and after ZGA. Key factors regulating M-decay and Z-decay pathways in mouse have similar expression pattern during human MZT, suggesting that YAP1-TEAD4 transcription activators, TUT4/7-mediated mRNA 3ʹ-oligouridylation, and BTG4/CCR4-NOT-induced mRNA deadenylation may also be involved in the regulation of human maternal mRNA stability. Decreased expression of these factors and abnormal accumulation of maternal transcripts are observed in the development-arrested embryos of patients who seek assisted reproduction. Defects of M-decay and Z-decay are detected with high incidence in embryos that are arrested at the zygote and 8-cell stages, respectively. In addition, M-decay is not found to be affected by maternal TUBB8 mutations, although these mutations cause meiotic cell division defects and zygotic arrest, which indicates that mRNA decay is regulated independent of meiotic spindle assembly. Considering the correlations between maternal mRNA decay defects and early developmental arrest of in vitro fertilized human embryos, M-decay and Z-decay pathway activities may contribute to the developmental potential of human preimplantation embryos.

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“…Mouse genome contains several L1 families, of which LINE1_Md_A, LINE1_Md_T(-F) and LINE1_Md_G(-F) are the most recent and contain full-length retrotransposition-competent LINE1 copies [59][60][61]. We examined expression of all full-length L1 elements with intact ORF in the reference C57Bl/6 genome in fully-grown oocytes by mapping our C57Bl/6 RNA-seq libraries directly on these elements (using RNA-seq of wild type oocytes from this work and from [62]). Perfectly mapping 50 nucleotide single end sequencing (50SE) showed low abundance of reads for the most expressed L1 elements from different families (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…) in fullygrown GV oocytes (125 PE from GSE116771[62], 50 SE from this work), RNA-seq reads were mapped onto genome with all sequences except the 2691 L1 elements masked. Only reads perfectly mapping to those sequences were retained 23.…”

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Restricted and non-essential redundancy of RNAi and piRNA pathways in mouse oocytes

Táborská

Pasulka

Malı́k

et al. 2019

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Germline genome defense evolves to recognize and suppress retrotransposons. One of defensive mechanisms is the PIWI-associated RNA (piRNA) pathway, which employs small RNAs for sequence-specific post-transcriptional and transcriptional repression. The loss of the piRNA pathway in mice causes male sterility while females remain fertile. Unlike spermatogenic cells, mouse oocytes have also RNA interference (RNAi), another small RNA pathway capable of retrotransposon suppression. To examine whether RNAi compensates the loss of the piRNA pathway in mouse oocytes, we produced a new RNAi pathway mutant Dicer SOM and crossed it with a catalytically-dead mutant of Mili, an essential piRNA gene. Normal follicular and oocyte in double mutants showed that RNAi does not suppress a strong piRNA knock-out phenotype.However, we observed redundant and non-redundant targeting of specific retrotransposons.Intracisternal A Particle retrotransposon was mainly targeted by the piRNA pathway, MT and RLTR10 retrotransposons were targeted mainly by RNAi. Importantly, only double mutants showed increased background levels of transcripts potentially originating from intact LINE-1 elements. Our results thus show that while both small RNA pathways are simultaneously expendable defense pathways for ovarian oocyte development, yet another transcriptional silencing mechanism must mediate LINE-1 repression in female germ cells.3 Author summaryRetrotransposons are mobile genomic parasites causing mutations. Germ cells need protection against retrotransposons to prevent heritable transmission of their new insertions. The piRNA pathway is an ancient germline defense system analogous to acquired immunity: once a retrotransposons jumps into a specific "genomic checkpoint", it is recognized and suppressed.Remarkably, the murine piRNA pathway is essential for spermatogenesis but not oocyte development. In contrast, zebrafish lacking the piRNA pathway do not develop any germ cells. It was hypothesized that RNA interference pathway could rescue oocyte development in mice lacking the piRNA pathway. RNA interference also targets retrotransposons and is particularly enhanced in mouse oocytes. To test this hypothesis, we engineered mice lacking both pathways and observed that oocytes in these mice develop normally, which argues against the hypothesis.Furthermore, analysis of individual retrotransposon groups revealed that in specific cases the two pathways can mutually compensate each other. However, this ability is restricted to specific retrotransposon groups and seems to evolve stochastically. Finally, our results also indicate that there must be yet another layer of retrotransposon silencing in mouse oocytes, which prevents high retrotransposon activity in the absence of piRNA and RNA interference pathways.

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Role of Cnot6l in maternal mRNA turnover

Abstract: Mice lacking Cnot6l, a deadenylase component of the CCR4–NOT complex, are viable, but females have ∼40% smaller litters. Cnot6l is a maternal-effect gene acting in maternal mRNA degradation.

Cited by 40 publications

References 45 publications

CNOT 6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte

CNOT 6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte

Dynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans

Restricted and non-essential redundancy of RNAi and piRNA pathways in mouse oocytes

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