An FGF4-FRS2α-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos

Murohashi, Michiko; Nakamura, Takahisa; Tanaka, Satoshi; Ichise, Taeko; Yoshida, Nobuaki; Yamamoto, Tadashi; Shibuya, Masabumi; Schlessinger, Joseph; Gotoh, Noriko

doi:10.1002/stem.247

Cited by 52 publications

(49 citation statements)

References 42 publications

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“…The addition of BMP4 to culture medium at early embryo stages boosted the establishment of trophoblastic cell lines in bovine, but there was no significant difference between untreated and BMP4 groups. Although mechanisms of enhancing BMP4 production of trophoblastic cells are lacking, some other growth factors/cytokines may be involved in this process because some growth factors play a crucial role for the ES cell lineages (Fujiwara et al 2002, Das et al 2007, Wu et al 2008, Hayashi et al 2010, Murohashi et al 2010. In this study, we added BMP4 during and after fertilization for 7 days and continuous culture from 6 days.…”

Section: Discussionmentioning

confidence: 99%

“…The efficiency was quite low and it generally seems to be difficult to raise trophoblastic cell lines in cattle. In this study, we used BMP4 to raise trophoblastic cell lines because exogenous BMP4-stimulated embryonic stem cells (ES) to become trophoblastic cells and promoted trophoblastic cell lines (Kurihara et al 1993, Murohashi et al 2010. The addition of BMP4 to culture medium at early embryo stages boosted the establishment of trophoblastic cell lines in bovine, but there was no significant difference between untreated and BMP4 groups.…”

Section: Discussionmentioning

confidence: 99%

“…Data labeled with different letters are significantly different from each other (P!0.05). Murohashi et al 2010). BMP4 combined with some other factors stimulates trophoblastic proliferation and differentiation (Fujiwara et al 2002, Das et al 2007, Wu et al 2008, Hayashi et al 2010, Murohashi et al 2010.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the protein plays important roles in the development of the early embryo and is a stimulatory factor for trophoblastic cell lineages (Xu et al 2002, Das et al 2007, Wu et al 2008, Hayashi et al 2010; however, its effects are still unclear (Kobayashi et al 2008. Various factors including BMP4 and transcription factors seem to participate in the differentiation of the trophoblastic cell lineage (Fujiwara et al 2002, Babaie et al 2007, Murohashi et al 2010. These previous reports urged us to examine the roles of BMP4 in the differentiation of early embryonic cells to trophoblastic lineage in cow.…”

Section: Introductionmentioning

confidence: 99%

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Bone morphogenetic protein 4 accelerates the establishment of bovine trophoblastic cell lines

Suzuki¹,

Koshi²,

Imai³

et al. 2011

Reproduction

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Trophoblastic cells play a crucial role in implantation and placentogenesis. A large proportion of the failures of conception in cows occur in the peri-implantation period, which are known as early embryo losses. In exploring this critical phenomenon, trophoblastic cell lines can provide substantial information. Unfortunately, there are few cell lines for this purpose in cattle because of the difficulty of raising successive cell stock in the long term. In this study, 12 new cell lines were established using bone morphogenetic protein 4 (BMP4). BMP4 stimulated embryonic cells to enter the trophoblastic cell lineage but there were no significant differences between intact and BMP4-treated groups. Only one out of 49 embryos developed trophoblastic cells in the intact group. Finally, 12 cell lines were maintained for around 30 passages, and they retained trophoblastic characteristics and expressed bovine trophoblastic genes: placental lactogen, interferon-t, pregnancy-associated glycoprotein 1, and prolactin-related protein 1. Although the gene expression patterns were different among cell lines and depended on the cells, there was no significant relationship between the expression intensities of genes and the treatment dose of BMP4. All of them expressed bovine POU domain class 5 transcription factor 1 and caudal-type homeobox 2. The expression of these genes was confirmed by quantitative RT-PCR and immunohistochemical detection. These results suggest that BMP4 is involved in the raising of trophoblast cell lines from early embryonic cells and the newly developed cell lines can provide different types of bovine trophoblastic cells with different cell lineages. This may constitute a significant new tool for the examination of trophoblastic differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bone morphogenetic protein 4 accelerates the establishment of bovine trophoblastic cell lines

Suzuki¹,

Koshi²,

Imai³

et al. 2011

Reproduction

View full text Add to dashboard Cite

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“…Previous experiments using trophoblast stem (TS) cells, the in vitro equivalent of EXE, showed that Ets2 is required for TS cell self-renewal and for maintaining the expression of several genes including Bmp4, Cdx2, Eomes, Esrrb and Pace4 39,40 . The transcription factors Cdx2 and Elf5 are also required in TS cells for their self-renewal, with Cdx2 also maintaining Bmp4 expression 5,[41][42][43] . We therefore examined the expression of all these genes in the EXE of type-II mutants at E6.7 and E7.5-7.75 and found that it was downregulated.…”

Section: Article Nature Communications | Doi: 101038/ncomms2646mentioning

confidence: 99%

Ets2-dependent trophoblast signalling is required for gastrulation progression after primitive streak initiation

Polydorou

Georgiades

2013

Nat Commun

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Although extraembryonic ectoderm trophoblast signals the embryo for primitive streak initiation, a prerequisite for gastrulation, it is unknown whether it also signals for the progression of gastrulation after primitive streak initiation. Here, using Ets2 À / À mice, we show that trophoblast signalling is also required in vivo for primitive streak elongation, completion of intraembryonic mesoderm epithelial-mesenchymal transition and the development of anterior primitive streak derivatives such as the node. We show that Ets2-dependent trophoblast signalling is required for the maintenance of high levels of Nodal and Wnt3 expression in the epiblast and for the induction of Snail expression in the primitive streak, between embryonic day 6.3 and 6.7. Within extraembryonic ectoderm trophoblast, Ets2 maintains the expression of the transcription factors Elf5, Cdx2 and Eomes, and that of the signalling molecule Bmp4. We propose a model that provides a genetic explanation as to how Ets2 in trophoblast mediates the progression of gastrulation within the epiblast.

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Inhibition of Phosphoinositide-3-Kinase Signaling Promotes the Stem Cell State of Trophoblast

et al. 2019

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Trophoblast stem cells (TSCs) are a heterogeneous cell population despite the presence of fibroblast growth factor (FGF) and transforming growth factor β (TGFB) as key growth factors in standard culture conditions. To understand what other signaling cascades control the stem cell state of mouse TSCs, we performed a kinase inhibitor screen and identified several novel pathways that cause TSC differentiation. Surprisingly, inhibition of phosphoinositide-3-kinase (PI3K) signaling increased the mRNA and protein expression of stem cell markers instead, and resulted in a tighter epithelial colony morphology and fewer differentiated cells. PI3K inhibition could not substitute for FGF or TGFB and did not affect phosphorylation of extracellular signal-regulated kinase, and thus acts independently of these pathways. Upon removal of PI3K inhibition, TSC transcription factor levels reverted to normal TSC levels, indicating that murine TSCs can reversibly switch between these two states. In summary, PI3K inhibition reduces the heterogeneity and seemingly heightens the stem cell state of TSCs as indicated by the simultaneous upregulation of multiple key marker genes and cell morphology. STEM CELLS 2019;37:1307-1318 SIGNIFICANCE STATEMENTTrophoblast stem cells (TSCs) are crucial to the development of a healthy placenta. However, not much is known about the signaling pathways that sustain their self-renewal and drive differentiation. This study uses a kinase inhibitor screen to identify novel pathways that regulate TSCs. Specifically, the authors identified that inhibition of phosphoinositide-3-kinase (PI3K) signaling increases the expression of stem cell markers in these cells. This is in contrast to other cell types, where PI3K inhibition leads to differentiation and apoptosis. The data suggest that just like embryonic stem cells, TSCs exhibit a dynamic stem cell state.

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An FGF4-FRS2α-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos

Cited by 52 publications

References 42 publications

Bone morphogenetic protein 4 accelerates the establishment of bovine trophoblastic cell lines

Bone morphogenetic protein 4 accelerates the establishment of bovine trophoblastic cell lines

Ets2-dependent trophoblast signalling is required for gastrulation progression after primitive streak initiation

Inhibition of Phosphoinositide-3-Kinase Signaling Promotes the Stem Cell State of Trophoblast

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