Inhibition of phosphorylated Ser473‐Akt from translocating into the nucleus contributes to 2‐cell arrest and defective zygotic genome activation in mouse preimplantation embryogenesis

Chen, Junming; Lian, Xiuli; Du, Juan; Xu, Shunqing; Wei, Jianen; Lili, Pang; Song, Chanchan; He, Lin; Wang, Shie

doi:10.1111/dgd.12273

Cited by 14 publications

(11 citation statements)

References 57 publications

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“…Mobilization of Akt2 from the cytoplasm to the nucleus at the two-cell stage may be necessary for the occurrence of the major wave of transcriptional activation of the zygotic genome and the progression through embryo cleavages, as recently suggested by Chen et al (2016). The presence and activity of Akt2 is necessary for embryo blastomere proliferation but not other morphogenetic processes such as compaction during later cleavage stages.…”

Section: Discussionmentioning

confidence: 78%

“…It was previously shown that the pronuclear presence of p-ser-473 Akt in one-cell embryos is required for the occurrence of the first mitosis (Baran, Fabian, & Rehak, 2013). On the other hand, the nuclear localization of p-ser-473 Akt in two-cell embryos was recently associated with the major wave of transcriptional activation of the zygotic genome and the progression through embryo cleavages (Chen et al, 2016). The Akt protein described by these groups is likely to be represented by either the Akt1 or the Akt2 isoform that fertilized eggs inherit from oogenesis (Cecconi et al, 2010;Cecconi et al, 2012), which is fully active (Fiorenza et al, 2008) and likely relevant at fertilization.…”

Section: Discussionmentioning

confidence: 99%

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Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos

Fiorenza

Russo

Narducci

et al. 2019

Journal Cellular Physiology

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Activation of Akt/Protein Kinase B (PKB) by phosphatidylinositol-3-kinase (PI3K) controls several cellular functions largely studied in mammalian cells, including preimplantation embryos. We previously showed that early mouse embryos inherit active Akt from oocytes and that the intracellular localization of this enzyme at the two-cell stage depends on the T-cell leukemia/lymphoma 1 oncogenic protein, Tcl1.We have now investigated whether Akt isoforms, namely Akt1, Akt2 and Akt3, exert a specific role in blastomere proliferation during preimplantation embryo development. We show that, in contrast to other Akt family members, Akt2 enters male and female pronuclei of mouse preimplantation embryos at the late one-cell stage and thereafter maintains a nuclear localization during later embryo cleavage stages.Depleting one-cell embryos of single Akt family members by microinjecting Akt isoform-specific antibodies into wild-type zygotes, we observed that: (a) Akt2 is necessary for normal embryo progression through cleavage stages; and (b) the specific nuclear targeting of Akt2 in two-cell embryos depends on Tcl1. Our results indicate that preimplantation mouse embryos have a peculiar regulation of blastomere proliferation based on the activity of the Akt/PKB family member Akt2, which is mediated by the oncogenic protein Tcl1. Both Akt2 and Tcl1 are essential for early blastomere proliferation and embryo development. K E Y W O R D SAkt/PKB isoforms, Akt2, mouse preimplantation embryos, Tcl1

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos

Fiorenza

Russo

Narducci

et al. 2019

Journal Cellular Physiology

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“…All three variants of Akt are expressed during mouse early development 50 , and the Akt pathway is present and functional in preimplantation embryos 51 . Chemical inhibition of Pi3k 52 or Akt 53 , or deletion of the master regulator genes, Pdk1 or Pten 54 , all block mouse embryo development at the 2-cell stage. Here, we observed that Akt signaling also is required for H3K36 trimethylation in 2-cell mouse embryos.…”

Section: Discussionmentioning

confidence: 99%

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

Oqani

Lin

Lee

et al. 2019

Sci Rep

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The mRNA processing and export factor, Iws1, interacts with the histone H3/H4 chaperone, Spt6 (Supt6 in mouse gene ontology) and recruits the lysine methyltransferase, Setd2, to chromatin to regulate H3K36me3. This recruitment is known to be crucial for pre-mRNA splicing and Iws1 has been shown to interact with REF1/Aly to mediate mRNA export. However, the role of this complex has not yet been examined in embryonic development. Here, we show that knockdown of either Iws1 or Supt6 blocked embryo development, primarily at the 8/16-cell stage, indicating that Iws1 and Supt6 are crucial for mouse preimplantation development. In the knockdown embryos, we observed decreases in pre-mRNA splicing, mRNA export and the expression of the lineage-specific transcription factor, Nanog. We found that either Iws1 or Supt6 are required for H3K36 trimethylation and that concurrent knockdown of both Iws1 and Supt6 blocks embryonic development at the 2-cell stage. We show that H3K36me3 is modulated by the Pi3k/Akt pathway, as inhibition of this pathway reduced the global level of H3K36me3 while activation of the pathway increased the level of this modification in 2-cell embryos. We observed that Iws1 interacts with nuclear Akt in early embryos, and herein propose that Akt modulates H3K36me3 through interaction with Iws1. Together, our results indicate that the Iws1 and Supt6 play crucial roles in embryonic genome activation, lineage specification, and histone modification during mouse early development.

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“…Failure to activate the zygotic genome is considered the main cause of 2-cell embryonic developmental arrest in mice [33,34]. It has been found that zygotic genome activation is regulated by H3K27me3, which affects the expression of zygotic genome activation genes (ZSCAN4, E1F1AX, HSPA1A, ERV4-2, and MYC), leading to the developmental arrest of 2-cell embryonic development in mice [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Wenshen Shengjing Decoction Improves Early Embryo Development by Maintaining Low H3K27me3 Levels in Sperm and Pronuclear Embryos of Spermatogenesis Impaired Mice

Sun

Gao

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Many ingredients in Wenshen Shengjing Decoction (WSSJD) can cause epigenetic changes in the development of different types of cells. It is not yet known whether they can cause epigenetic changes in sperms or early embryos. Here, we investigated the role of WSSJD in epigenetic modifications of sperms or early embryos and early embryo development. A mouse model with spermatogenesis disorders was established with cyclophosphamide (CPA). WSSJD was administrated for 30 days. The male model mice after the treatment were mated with the female mice treated with superovulation. The embryo development rate of each stage was calculated. Immunofluorescence staining was used to detect the expression of H3K27me3 in sperm, pronuclear embryos, and 2-cell embryos. Western blotting was used to detect the expression of histone demethylase KDM6A and methyltransferase EZH2 in 2-cell embryos with developmental arrest. The expressions of zygotic genome activation genes (ZSCAN4, E1F1AX, HSPA1A, ERV4-2, and MYC) in 2-cell embryos with developmental arrest were analyzed with qRT-PCR. Comparing with the control group, CPA destroyed the development of seminiferous epithelium, significantly increased the expression level of H3K27me3 in sperm, reduced the expression ratio of H3K27me3 in female and male pronuclei, delayed the development of 2-cell embryos, and increased the developmental arrest rate and degeneration rate of 2-cell embryos. Moreover, the expressions of EZH2 and H3K27me3 were significantly increased in the 2-cell embryos with developmental arrest, and the expression of zygotic genome activation genes (ZSCAN4, E1F1AX, HSPA1A, ERV4-2, and MYC) was significantly decreased. Compared with the CPA group, WSSJD promoted the development of seminiferous epithelium, maintained a low level of H3K27me3 modification in sperm and male pronucleus, significantly increased the development rate of 2-cell embryos and 3-4 cell embryos, and reduced the developmental arrest rate and degeneration rate of 2-cell embryos. WSSJD may promote early embryonic development by maintaining a low level of H3K27me3 modification in sperm and male pronucleus and regulating the zygotic genome activation in mice with spermatogenesis disorders induced by CPA.

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Inhibition of phosphorylated Ser473‐Akt from translocating into the nucleus contributes to 2‐cell arrest and defective zygotic genome activation in mouse preimplantation embryogenesis

Cited by 14 publications

References 57 publications

Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos

Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos

Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation

Wenshen Shengjing Decoction Improves Early Embryo Development by Maintaining Low H3K27me3 Levels in Sperm and Pronuclear Embryos of Spermatogenesis Impaired Mice

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