Lymphoid Enhancer Factor 1-Mediated Wnt Signaling Promotes the Initiation of Trophoblast Lineage Differentiation in Mouse Embryonic Stem Cells

He, Shuyang; Pant, Disha; Schiffmacher, Andrew T.; Meece, Ashley; Keefer, Carol L.

doi:10.1634/stemcells.2007-0356

Cited by 61 publications

(50 citation statements)

References 43 publications

(59 reference statements)

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“…Induction of the Ras-MAPK pathway in Tcfap2c-deficient ESCs should shed light on this molecular cascade. In addition to Tead4 (27), Wnt signaling is able to trigger Cdx2 expression and TE lineage differentiation in ESCs (14). Data from Xenopus show that Tcfap2c is also induced by Wnt signaling (42); therefore, expression of both Cdx2 and Tcfap2c may be initiated in response to Wnt signaling.…”

Section: Tcfap2cmentioning

confidence: 99%

The Transcription Factor TCFAP2C/AP-2γ Cooperates with CDX2 To Maintain Trophectoderm Formation

Kuckenberg

Buhl

Woynecki

et al. 2010

Molecular and Cellular Biology

143

157

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In mammals, cell lineage specification is established at the blastocyst stage. At this stage, transcription factor Cdx2 represses pluripotency genes, thus promoting extraembryonic trophoblast fate. Recently, transcription factor Gata3 was shown to act in a parallel pathway in promoting trophoblast cell fate, suggesting that there are more factors working in the trophoblast lineage. Here, we report that the transcription factor Tcfap2c is expressed at a high level in the trophectoderm and is able to induce trophoblast fate in embryonic stem cells. Trophoblast fate induced by Tcfap2c does not require Cdx2 and vice versa, suggesting that the molecules act in alternative pathways. However, both Tcfap2c and Cdx2 are required for the upregulation of Elf5, a marker of trophoblast stem cell maintenance, suggesting that both factors are required for stable trophoblast induction. Tcfap2c-induced trophoblast-like cells are stable in long-term culture, indicating that they are capable of self-renewal. Tcfap2c-controlled trophoblast maintenance involves the induction of Cdx2 and the repression of the pluripotency factor Nanog. Tcfap2c-induced trophoblast-like cells differentiate to trophoblast derivatives in vitro and contribute to the trophectoderm in blastocysts in vivo. Taken together, these observations suggest that Tcfap2c and Cdx2 cooperate to override the pluripotency program and establish the extraembryonic trophoblast maintenance program in murine embryos.The earliest cell fate decision during mammalian development is the establishment of the first two cell lineages of the blastocyst prior to implantation. The inner cell mass (ICM) forms the embryo proper as well as extraembryonic endodermal components of the placenta, whereas the trophectoderm (TE) gives rise to the fetal portion of the placenta, a structure unique to mammalian development (11). Self-renewing embryonic stem cell (ESC) and trophoblast stem cell (TSC) lines have been derived from each of these lineages in vitro (10,23,36). TSCs exhibit the potential to differentiate into multiple trophoblastic cell types in vitro, participate in the normal development of chimeras, and contribute exclusively to the trophoblastic component of the placenta in vivo (28,36).At the genetic level, key factors that establish and maintain the TE lineage in the early embryo have been identified. Based on so far unknown positional information, the Hippo signaling pathway component YAP (Yes kinase-associated protein 1, a coactivator of Tead4) is phosphorylated by LATS (large tumor suppressor, a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of protein kinase A/PKG/PKC kinases) and becomes cytoplasmic in the inner cells of the morula. In outer blastomeres, YAP remains in the nucleus and associates with and activates TEAD4 (26), which in turn transactivates the expression of the transcription factor CDX2 (caudal-related homeobox 2) (27, 40). CDX2 represses pluripotency markers such as Oct3/4 (Pou5f1) and Nanog (and vice versa), which leads to the maintenance of the restrict...

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Section: Tcfap2cmentioning

confidence: 99%

The Transcription Factor TCFAP2C/AP-2γ Cooperates with CDX2 To Maintain Trophectoderm Formation

Kuckenberg

Buhl

Woynecki

et al. 2010

Molecular and Cellular Biology

143

157

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“…More work needs to be done to determine if this derepression of trophectoderm genes is BMP-dependent. Mouse ES cells do not readily contribute to the trophectoderm lineages when introduced to a blastocyst; however, some differentiation conditions have been described to allow such differentiation in vitro (54,55). Thus, further work is needed to ascertain whether autocrine Nodal signaling inhibits the propensity of ES cells to differentiate to a trophectoderm pathway, and if this function is achieved by attenuating BMP activity.…”

Section: Smad7 Is the Critical Component Of Nodal Regulation Of Bmp Amentioning

confidence: 99%

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

Galvin

Travis

Yee

et al. 2010

Journal of Biological Chemistry

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Members of the transforming growth factor-␤ superfamily play essential roles in both the pluripotency and differentiation of embryonic stem (ES) cells. Although bone morphogenic proteins (BMPs) maintain pluripotency of undifferentiated mouse ES cells, the role of autocrine Nodal signaling is less clear. Pharmacological, molecular, and genetic methods were used to further understand the roles and potential interactions of these pathways. Treatment of undifferentiated ES cells with SB431542, a pharmacological inhibitor of Smad2 signaling, resulted in a rapid reduction of phosphorylated Smad2 and altered the expression of several putative downstream targets. Unexpectedly, inhibition of the Nodal signaling pathway resulted in enhanced BMP signaling, as assessed by Smad1/5 phosphorylation. SB431542-treated cells also demonstrated significant induction of the Id genes, which are known direct targets of BMP signaling and important factors in ES cell pluripotency. Inhibition of BMP signaling decreased the SB431542-mediated phosphorylation of Smad1/5 and induction of Id genes, suggesting that BMP signaling is necessary for some Smad2-mediated activity. Because Smad7, a known inhibitory factor to both Nodal and BMP signaling, was down-regulated following inhibition of Nodal-Smad2 signaling, the contribution of Smad7 to the cross-talk between the transforming growth factor-␤ pathways in ES cells was examined. Biochemical manipulation of Smad7 expression, through shRNA knockdown or inducible gene expression, significantly reduced the SB431542-mediated phosphorylation of Smad1/5 and induction of the Id genes. We conclude that autocrine Nodal signaling in undifferentiated mouse ES cells modulates the vital pluripotency pathway of BMP signaling. Mouse embryonic stem (ES)2 cells are derived from the inner cell mass of the early blastocyst. It is from the inner cell mass that the germ layers arise to produce all cell types of the adult. The capacity of ES cells to either self-renew or differentiate into cells of the three germ layers provides an excellent tool for studying early embryonic development, including self-renewal and pluripotency (1). Some of the essential factors controlling ES cell pluripotency have been identified; however, additional work is necessary to identify other functional signaling pathways that impinge upon the ES cell phenotype, to determine genes that are regulated by these pathways, and to discover how the various pathways interact. Applications of this work will yield insights into the promising use of stem cells for regenerative therapies.ES cells can be maintained as pluripotent cells when grown on mitotically inactivated embryonic fibroblasts or when grown in media supplemented with leukemia inhibitory factor (LIF (2, 3)). Additionally, under serum-free culture conditions, signaling through the bone morphogenetic protein (BMP) pathway is essential for maintaining mouse ES cell pluripotency (4, 5). The combination of LIF and BMP4 inhibits multiple differentiation-inductive signals, a capability that...

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“…[86][87][88] Moreover, Wnt signalling may play a critical role in trophoblast development because Wnt-3A was shown to promote trophectoderm formation in embryonic stem cells by inducing the critical transcription factor Cdx2 in a LEF-1-dependent manner. 89 However, Wnt signalling may not be only required for early trophoblast lineage determination but also control function of differentiated trophoblast subtypes, such as the invasive, EVT. Recent studies identified nuclear b-catenin in a subset of EVT in vivo as well as in vitro after outgrowth from chorionic villous explant cultures.…”

Section: -66mentioning

confidence: 99%

REVIEW ARTICLE: Governing the Invasive Trophoblast: Current Aspects on Intra‐ and Extracellular Regulation

Fitzgerald

Germeyer

Huppertz

et al. 2010

American J Rep Immunol

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Citation Fitzgerald JS, Germeyer A, Huppertz B, Jeschke U, Knöfler M, Moser G, Scholz C, Sonderegger S, Toth B, Markert UR. Governing the invasive trophoblast: current aspects on intra‐ and extracellular regulation. Am J Reprod Immunol 2010This review summarizes several aspects especially of regulating factors governing trophoblast invasion. Those include the composition of the extracellular matrix containing a variety of matrix metalloproeinases and their inhibitors, but also intracellular signals. Furthermore, a newly described trophoblast subtype, the endoglandular trophoblast, is presented. Its presence may provide a possible mechanism for opening and connecting uterine glands into the intervillous space. Amongst others, two intracellular signalling pathways are crucial for regulation of trophoblast functions and development: Wnt‐ and signal transducer and activator of transcription (STAT)3 signalling. Wnt signalling promotes implantation, placentation and trophoblast differentiation. Several Wnt‐dependent cascades and regulatory mechanisms display different functions in trophoblast cells. The STAT3 signalling system is fundamental for induction and regulation of invasiveness in physiological trophoblastic cells, but also in tumours. The role of galectins (Gal) in trophoblast regulation and placenta development comes increasingly into focus. The Gal‐ 1–4, 7–10 and 12–14 have been detected in humans. Detailed information is only available for Gal‐1, ‐2, ‐3, ‐4, ‐9 and ‐12 in endometrium and decidua. Gal‐1, ‐3 and ‐13 (‐14) have been detected and studied in trophoblast cells.

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Lymphoid Enhancer Factor 1-Mediated Wnt Signaling Promotes the Initiation of Trophoblast Lineage Differentiation in Mouse Embryonic Stem Cells

Cited by 61 publications

References 43 publications

The Transcription Factor TCFAP2C/AP-2γ Cooperates with CDX2 To Maintain Trophectoderm Formation

The Transcription Factor TCFAP2C/AP-2γ Cooperates with CDX2 To Maintain Trophectoderm Formation

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

REVIEW ARTICLE: Governing the Invasive Trophoblast: Current Aspects on Intra‐ and Extracellular Regulation

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