Wenzel, P. L. et al. Rb is critical in a mammalian tissue stem cell population. Genes Dev. 21, 85-97

Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Genes & Development (Impact Factor: 10.8). 02/2007; 21(1):85-97. DOI: 10.1101/gad.1485307
Source: PubMed


The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5). Here we show that the specific loss of Rb in trophoblast stem (TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb(-/-) embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.

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Available from: James C Cross, Oct 04, 2015
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    • "Unbiased identification of genes bound by E2F3 (including both the E2F3a and E2F3b isoforms) have to our knowledge been reported to date only in C2C12 myoblasts and myotubes (Asp et al., 2009), in mouse embryonic fibroblasts (von Eyss et al., 2012) and in primary murine NPCs (Julian et al., 2015). E2F3a&b, however, exhibit pivotal roles in a number of tissue systems and cellular processes, including gross mammalian embryonic development (Tsai et al., 2008), neurogenesis (Chen et al., 2007; McClellan et al., 2007, 2009; Julian et al., 2013), myogenesis (Asp et al., 2009), Sertoli cell maturation and survival (Rotgers et al., 2014), and maintenance of trophoblast stem cells (Wenzel et al., 2007). Given its broad functional roles, unbiased identification of E2F3 target genes in a greater diversity of cell types will therefore be greatly informative of the conserved and possible tissue-specific mechanisms by which E2F/PPs regulate cell fate decisions. "
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    ABSTRACT: E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general 'multi-purpose' cell fate genes but can execute tissue-and cell type-specific gene regulatory programs.
    Frontiers in Genetics 04/2015; 6:161. DOI:10.3389/fgene.2015.00161
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    • "Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. Specific loss of mouse pRB1 gene in trophoblast stem cells resulted in an overexpansion of trophoblasts, profound placental abnormalities, and eventually fetal death (Wenzel et al., 2007). Loss of pRB1 resulted in an increase of E2F3 expression and the combined depletion of pRB1 and E2F3 in trophoblast stem cells rescued the pRB1 mutant phenotypes by restoration of placental development and by extending the lifespan of embryos. "
    Future Aspect of Tumor Suppressor Gene, 1 edited by Yue Cheng, 04/2013: chapter 4: pages 75-96; InTech., ISBN: 978-953-51-1063-7
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    • "It thus appears that RB has a cell-autonomous and non-cell-autonomous role depending on cell and tissue type. Effect of RB loss on the pancreas, with or without normal placental compensation, was not addressed in either the original (Clarke et al, 1992; Jacks et al, 1992; Lee et al, 1992) or the subsequent placental rescue studies (Wu et al, 2003; Wenzel et al, 2007). To examine the effects of RB loss on pancreatic development without the placental contribution, we established a pancreatic rudiment ex vivo culture system. "
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    ABSTRACT: RB is a key substrate of Cdks and an important regulator of the mammalian cell cycle. RB either represses E2Fs that promote cell proliferation or enhances the activity of cell-specific factors that promote differentiation, although the mechanism that facilitates this dual interaction is unclear. Here, we demonstrate that RB associates with and stabilizes pancreatic duodenal homeobox-1 (Pdx-1) that is essential for embryonic pancreas development and adult β-cell function. Interestingly, Pdx-1 utilizes a conserved RB-interaction motif (RIM) that is also present in E2Fs. Point mutations within the RIM reduce RB-Pdx-1 complex formation, destabilize Pdx-1 and promote its proteasomal degradation. Glucose regulates RB and Pdx-1 levels, RB/Pdx-1 complex formation and Pdx-1 degradation. RB occupies the promoters of β-cell-specific genes, and knockdown of RB results in reduced expression of Pdx-1 and its target genes. Further, RB-deficiency in vivo results in reduced pancreas size due to decreased proliferation of Pdx-1(+) pancreatic progenitors, increased apoptosis and aberrant expression of regulators of pancreatic development. These results demonstrate an unanticipated regulatory mechanism for pancreatic development and β-cell function, which involves RB-mediated stabilization of the pancreas-specific transcription factor Pdx-1.
    The EMBO Journal 03/2011; 30(8):1563-76. DOI:10.1038/emboj.2011.57 · 10.43 Impact Factor
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