Foxd3 is required in the trophoblast progenitor cell lineage of the mouse embryo

Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104-6058, USA.
Developmental Biology (Impact Factor: 3.55). 10/2005; 285(1):126-37. DOI: 10.1016/j.ydbio.2005.06.008
Source: PubMed


The murine blastocyst contains two nonoverlapping pools of progenitor cells: the embryonic component contributes to the fetus and generates embryonic stem cells in vitro, whereas the extraembryonic pool contributes to the placenta and generates trophoblast stem cells in vitro. The transcriptional repressor Foxd3 is required for maintenance of the epiblast and the in vitro establishment of embryonic stem cell lines. Here, we demonstrate that Foxd3 is also required in the trophoblast lineage. Trophoblast progenitors in Foxd3-/- embryos do not self-renew and are not multipotent, but instead give rise to an excess of trophoblast giant cells. Injection of Foxd3-/- blastocysts with wild type ES cells fails to rescue Foxd3-/- placentas and such chimeras die around 10 days of embryogenesis. These results indicate an essential role for Foxd3 in two nonoverlapping progenitor cell populations that require different secreted factors to maintain their multipotent properties in vitro and give rise to divergent tissues in vivo. Moreover, this provides support for the hypothesis that there are conserved molecular mechanisms for maintaining the self-renewing properties of diverse progenitor cell types.

Download full-text


Available from: Patricia Ann Labosky
  • Source
    • "Arman et al. (1998) Foxd3 Forkhead transcription factor Mutants die at E6.5, TGC number increased. Tompers et al. (2005) Hop/NECC1 Homeodomain transcription factor Reduced spongiotrophoblast but TGC number increased Asanoma et al. (2007) Mash2/Ascl2 Basic helix-loop-helix transcription factor Mutants die by E10.5, TGC number increased, spongiotrophoblast, glycogen trophoblast and labyrinth decreased Guillemot et al. (1994, Oh-McGinnis et al. (2011), Scott et al. (2000), Tanaka et al. (1997) Nodal Transforming growth factor β superfamily member Mutant die at E9.5, TGC number increased. Guzman-Ayala et al. (2004), Ma et al. (2001) p53 Tumor suppressor protein, transcription factor Mutants die postnatally, spongiotrophoblast reduced but TGC number increased Komatsu et al. (2007), Soloveva and Linzer (2004) Socs3 Suppressor of cytokine signaling protein Mutants die at E13.5, with reduced labyrinth and spongiotrophoblast, TGC number increased. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The maternal vasculature within the placenta in primates and rodents is unique because it is lined by fetal cells of the trophoblast lineage and not by maternal endothelial cells. In addition to trophoblast cells that invade the uterine spiral arteries that bring blood into the placenta, other trophoblast subtypes sit at different levels of the vascular space. In mice, at least five distinct subtypes of trophoblast cells have been identified which engage maternal endothelial cells on the arterial and venous frontiers of the placenta, but which also form the channel-like spaces within it through a process analogous to formation of blood vessels (vasculogenic mimicry). These cells are all large, post-mitotic trophoblast giant cells. In addition to assuming endothelial cell-like characteristics (endothelial mimicry), they produce dozens of different hormones that are thought to regulate local and systemic maternal adaptations to pregnancy. Recent work has identified distinct molecular pathways in mice that regulate the morphogenesis of trophoblast cells on the arterial and venous sides of the vascular circuit that may be analogous to specification of arterial and venous endothelial cells.
    Full-text · Article · Jan 2014 · Developmental Biology
  • Source
    • "Immunocytochemistry to detect Foxd3 protein was performed following standard techniques (Liu and Labosky, 2008) with the Foxd3 primary antiserum (Tompers et al., 2005) diluted in blocking (5% normal donkey serum in PBS) solution (1:1000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding gene regulatory networks controlling properties of pluripotent stem cells will facilitate development of stem cell-based therapies. The transcription factor Foxd3 is critical for maintenance of self-renewal, survival, and pluripotency in murine embryonic stem cells (ESCs). Using a conditional deletion of Foxd3 followed by gene expression analyses, we demonstrate that genes required for several developmental processes including embryonic organ development, epithelium development, and epithelial differentiation were misregulated in the absence of Foxd3. Additionally, we identified 6 novel targets of Foxd3 (Sox4, Safb, Sox15, Fosb, Pmaip1 and Smarcd3). Finally, we present data suggesting that Foxd3 functions upstream of genes required for skeletal muscle development. Together, this work provides further evidence that Foxd3 is a critical regulator of murine development through the regulation of lineage specific differentiation.
    Full-text · Article · Nov 2013 · Stem Cell Research
  • Source
    • "Furthermore, FOXD3 and TERT are highlyexpressed in our iTP cells. Reports have confirmed that FOXD3 is required for trophoblast progenitor cells self-renewal and multidifferentiation [42], whereas TERT is required for trophoblast progenitor cell self-renewal [43]. These data further suggest that our iTP cells have retained the progenitor status. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal trophoblast lineage proliferation and differentiation in early pregnancy have been associated with the pathogenesis of placenta diseases of pregnancy. However, there is still a gap in understanding the molecular mechanisms of early placental development due to the limited primary trophoblast cultures and fidelity of immortalized trophoblast lines. Trophoblasts stem (TS) cells, an in vitro model of trophectoderm that can differentiate into syncytiotrophoblasts and extravillous trophoblasts, can be an attractive tool for early pregnancy research. TS cells are well established in mouse but not in humans due to insufficient knowledge of which trophoblast lineage-specific transcription factors are involved in human trophectoderm (TE) proliferation and differentiation. Here, we applied induced pluripotent stem cell technique to investigate the human trophoblast lineage-specific transcription factors. We established human induced trophoblast progenitor (iTP) cells by direct reprogramming the fibroblasts with a pool of mouse trophoblast lineage-specific transcription factors consisting of CDX2, EOMES, and ELF5. The human iTP cells exhibit epithelial morphology and can be maintained in vitro for more than 2 months. Gene expression profile of these cells was tightly clustered with human trophectoderms but not with human neuron progenitor cells, mesenchymal stem cells, or endoderm cells. These cells are capable of differentiating into cells with an invasive capacity, suggesting extravillous trophoblasts. They also form multi-nucleated cells which secrete human chorionic gonadotropin and estradiol, suggesting syncytiotrophoblasts. Our results provide the evidence that transcription factors CDX2 and EOMES may play critical roles in human iTP cell generation.
    Full-text · Article · Jan 2013 · Biochemical and Biophysical Research Communications
Show more