A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

Karasek, Challis; Ashry, Mohamed; Driscoll, Chad S; Knott, Jack H.

doi:10.1093/molehr/gaaa052

Cited by 23 publications

(19 citation statements)

References 92 publications

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“…3f ), we suspected that the differentiation of preimplantation embryos could be regulated by BZW1. Immunofluorescence staining revealed the levels and localization of OCT4, NANOG, and CDX2 proteins, all of which are essential for the differentiation of ICM and TE 27 , 28 . The results suggest that OCT4 and NANOG protein levels decreased in Bzw1 -knockdown embryos with irregular localization during the 8-cell to blastocyst stages, whereas CDX2 was unaffected (Fig.…”

Section: Resultsmentioning

confidence: 99%

Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation

Zhang

et al. 2022

Nat Commun

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Protein synthesis is an essential step in gene expression during the development of mammalian preimplantation embryos. This is a complex and highly regulated process. The accuracy of the translation initiation codon is important in various gene expression programs. However, the mechanisms that regulate AUG and non-AUG codon initiation in early embryos remain poorly understood. BZW1 is a key factor in determining the mRNA translation start codon. Here, we show that BZW1 is essential for early embryonic development in mice. Bzw1-knockdown embryos fail to undergo compaction, and show decreased blastocyst formation rates. We also observe defects in the differentiation capacity and implantation potential after Bzw1 interference. Further investigation revealed that Bzw1 knockdown causes the levels of translation initiation with CUG as the start codon to increase. The decline in BZW1 levels result in a decrease in protein synthesis in preimplantation embryos, whereas the total mRNA levels are not altered. Therefore, we concluded that BZW1 contributes to protein synthesis during early embryonic development by restricting non-AUG translational initiation.

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Section: Resultsmentioning

confidence: 99%

Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation

Zhang

et al. 2022

Nat Commun

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“…In general, unphosphorylated YAP translocates to the nucleus, whereas phosphorylated YAP undergoes cytoplasmic inactivation [ 11 , 13 , 14 ]. Here we detected YAP only in nuclei in day 6 and day 8 bovine embryos, when using an anti-YAP antibody that recognizes both phosphorylated and unphosphorylated YAP; it is possible that YAP is rapidly removed from the cytoplasm after phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, studies have revealed that the Hippo pathway is involved in follicular activation and follicle growth [ 7 , 8 , 9 ]. In addition, emerging evidence has indicated that the Hippo-YAP signaling pathway also plays an essential role in controlling the expression of the key transcription factors in first-lineage segregation (ICM and TE differentiation) during mouse preimplantation development [ 10 , 11 , 12 , 13 ]. In the cells on the outside of the morula, where the Hippo pathway is inactive, YAP/TAZ remain unphosphorylated and migrate to the nucleus to bind the transcriptional coactivator TEAD4 facilitating Cdx2 expression, and subsequently driving them to a TE fate [ 11 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, emerging evidence has indicated that the Hippo-YAP signaling pathway also plays an essential role in controlling the expression of the key transcription factors in first-lineage segregation (ICM and TE differentiation) during mouse preimplantation development [ 10 , 11 , 12 , 13 ]. In the cells on the outside of the morula, where the Hippo pathway is inactive, YAP/TAZ remain unphosphorylated and migrate to the nucleus to bind the transcriptional coactivator TEAD4 facilitating Cdx2 expression, and subsequently driving them to a TE fate [ 11 , 13 , 14 ]. Moreover, it has been reported that both maternal and zygotic-derived YAP promote CDX2 expression, and that Tead4 -deleted mouse embryos fail to develop TE [ 10 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidic Acid Accelerates Bovine In Vitro-Produced Blastocyst Formation through the Hippo/YAP Pathway

Tol

Oei

et al. 2021

IJMS

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The segregation of trophectoderm (TE) and inner cell mass in early embryos is driven primarily by the transcription factor CDX2. The signals that trigger CDX2 activation are, however, less clear. In mouse embryos, the Hippo-YAP signaling pathway is important for the activation of CDX2 expression; it is less clear whether this relationship is conserved in other mammals. Lysophosphatidic acid (LPA) has been reported to increase YAP levels by inhibiting its degradation. In this study, we cultured bovine embryos in the presence of LPA and examined changes in gene and protein expression. LPA was found to accelerate the onset of blastocyst formation on days 5 and 6, without changing the TE/inner cell mass ratio. We further observed that the expression of TAZ and TEAD4 was up-regulated, and YAP was overexpressed, in LPA-treated day 6 embryos. However, LPA-induced up-regulation of CDX2 expression was only evident in day 8 embryos. Overall, our data suggest that the Hippo signaling pathway is involved in the initiation of bovine blastocyst formation, but does not affect the cell lineage constitution of blastocysts.

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“…Malfunctioning of Hippo components has been associated with defects in TE as well as inner cell mass (ICM) specification leading preimplantation developmental arrest [ 23 , 24 ]. Recently, Hippo has been reported to translate positional information into indispensable transcriptional circuits specifying the trophectoderm in preimplantation embryos [ 25 , 26 ]. Molecular orchestration between Hippo and other signaling pathways is imperative to trophectoderm restriction [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular regulation of trophoblast stem cell self-renewal and giant cell differentiation by the Hippo components YAP and LATS1

Basak

Ain

2022

Stem Cell Res Ther

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Background Trophoblast stem cells (TSCs), the precursors of trophoblast cells of placenta, possess the potential to differentiate into various trophoblastic subtypes in vitro. Establishment of extraembryonic trophoblastic lineage is preceded by the “outside versus inside” positional information in preimplantation embryos, critically synchronized by the Hippo components. Abundant expression of Hippo effector YAP in TSCs and differentiated cells with paucity of information on Hippo regulation of TSC proliferation/differentiation led us test the hypothesis that Hippo dynamics is one of the regulators of TSC proliferation/differentiation. Methods Blastocyst-derived murine TSCs were used. Dynamics of Hippo components were analyzed using immunofluorescence, western blotting, immunoprecipitation, qRT-PCR. Interaction studies were performed using full-length and deletion constructs. BrdU incorporation assay, flow cytometry-based polyploidy analysis and confocal microscopy were used to decipher the underlying mechanism. Results YAP translocates to the nucleus in TSCs and utilizes its WW2 domain to interact with the PPQY motif of the stemness factor, CDX2. YAP limits TSC proliferation with associated effect on CDX2 target CyclinD1. Trophoblast giant cells (TGC) differentiation is associated with cytoplasmic retention of YAP, heightened pYAPSer127, decrease in the level of the core Hippo component, LATS1, which thereby impedes LATS1-LIMK2 association. Decreased LATS1-LIMK2 complex formation in TGCs was associated with elevated pLIMK2Thr505 as well as its target pCOFILINSer3. Precocious overexpression of LATS1 during trophoblast differentiation decreased TGC marker, Prl2c2, diminished pLIMK2Thr505 and inactive COFILIN (pCOFILINSer3) while COFILIN-phosphatase, CHRONOPHIN remained unchanged. LATS1 overexpression inhibited trophoblast endoreduplication with smaller-sized TGC-nuclei, lower ploidy level and disintegrated actin filaments. Inhibition of LIMK2 activity recapitulated the effects of LATS1 overexpression in trophoblast cells. Conclusion These results unveil a multilayered regulation of trophoblast self-renewal and differentiation by the Hippo components.

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A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

Cited by 23 publications

References 92 publications

Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation

Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation

Lysophosphatidic Acid Accelerates Bovine In Vitro-Produced Blastocyst Formation through the Hippo/YAP Pathway

Molecular regulation of trophoblast stem cell self-renewal and giant cell differentiation by the Hippo components YAP and LATS1

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