Skip to main content
SpringerLink
Log in

The Role of Runx1 in Embryonic Blood Cell Formation

  • Chapter
  • First Online:
RUNX Proteins in Development and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 962))

Abstract

The de novo generation of hematopoietic stem and progenitor cells (HSPC) occurs solely during embryogenesis from a population of epithelial cells called hemogenic endothelium (HE). During midgestation HE cells in multiple intra- and extraembryonic vascular beds leave the vessel wall as they transition into HSPCs in a process termed the endothelial to hematopoietic transition (EHT). Runx1 expression in HE cells orchestrates the transcriptional switch necessary for the transdifferentiation of endothelial cells into functional HSPCs. Runx1 is widely considered the master regulator of developmental hematopoiesis because it plays an essential function during specification of the hematopoietic lineage during embryogenesis. Here we review the role of Runx1 in embryonic HSPC formation, with a particular focus on its role in hemogenic endothelium.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aird, W. C. (2012). Endothelial cell heterogeneity. Cold Spring Harbor Perspectives in Medicine, 2, a006429.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bee, T., Ashley, E. L., Bickley, S. R., Jarratt, A., Li, P. S., Sloane-Stanley, J., et al. (2009a). The mouse Runx1 +23 hematopoietic stem cell enhancer confers hematopoietic specificity to both Runx1 promoters. Blood, 113, 5121–5124.

    Article  CAS  PubMed  Google Scholar 

  • Bee, T., Liddiard, K., Swiers, G., Bickley, S. R., Vink, C. S., Jarratt, A., et al. (2009b). Alternative Runx1 promoter usage in mouse developmental hematopoiesis. Blood Cells, Molecules & Diseases, 43, 35–42.

    Article  CAS  Google Scholar 

  • Bee, T., Swiers, G., Muroi, S., Pozner, A., Nottingham, W., Santos, A. C., et al. (2010). Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis. Blood, 115, 3042–3050.

    Article  CAS  PubMed  Google Scholar 

  • Ben-Ami, O., Pencovich, N., Lotem, J., Levanon, D., & Groner, Y. (2009). A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis. Proceedings of the National Academy of Sciences of the United States of America, 106, 238–243.

    Article  CAS  PubMed  Google Scholar 

  • Bertrand, J. Y., Chi, N. C., Santoso, B., Teng, S., Stainier, D. Y., & Traver, D. (2010). Haematopoietic stem cells derive directly from aortic endothelium during development. Nature, 464, 108–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boisset, J. C., Van Cappellen, W., Andrieu-Soler, C., Galjart, N., Dzierzak, E., & Robin, C. (2010). In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature, 464, 116–120.

    Article  CAS  PubMed  Google Scholar 

  • Boisset, J. C., Clapes, T., Klaus, A., Papazian, N., Onderwater, J., Mommaas-Kienhuis, M., et al. (2015). Progressive maturation toward hematopoietic stem cells in the mouse embryo aorta. Blood, 125, 465–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bos, F. L., Hawkins, J. S., & Zovein, A. C. (2015). Single-cell resolution of morphological changes in hemogenic endothelium. Development, 142, 2719–2724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bresciani, E., Carrington, B., Wincovitch, S., Jones, M., Gore, A. V., Weinstein, B. M., et al. (2014). CBFβ and RUNX1 are required at 2 different steps during the development of hematopoietic stem cells in zebrafish. Blood, 124, 70–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai, Z., De Bruijn, M., Ma, X., Dortland, B., Luteijn, T., Downing, R. J., & Dzierzak, E. (2000). Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo. Immunity, 13, 423–431.

    Article  CAS  PubMed  Google Scholar 

  • Canon, J., & Banerjee, U. (2003). In vivo analysis of a developmental circuit for direct transcriptional activation and repression in the same cell by a Runx protein. Genes & Development, 17, 838–843.

    Article  CAS  Google Scholar 

  • Casanello, P., Schneider, D., Herrera, E. A., Uauy, R., & Krause, B. J. (2014). Endothelial heterogeneity in the umbilico-placental unit: DNA methylation as an innuendo of epigenetic diversity. Frontiers in Pharmacology, 5, 49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Castilla, L. H., Wijmenga, C., Wang, Q., Stacy, T., Speck, N. A., Eckhaus, M., et al. (1996). Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell, 87, 687–696.

    Article  CAS  PubMed  Google Scholar 

  • Challen, G. A., & Goodell, M. A. (2010). Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells. Experimental Hematology, 38, 403–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan, S. S., & Kyba, M. (2013). What is a master regulator? Journal of Stem Cell Research and Therapy, 3, 114.

    Google Scholar 

  • Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E., & Speck, N. A. (2009). Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature, 457, 887–891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chi, J. T., Chang, H. Y., Haraldsen, G., Jahnsen, F. L., Troyanskaya, O. G., Chang, D. S., et al. (2003). Endothelial cell diversity revealed by global expression profiling. Proceedings of the National Academy of Sciences of the United States of America, 100, 10623–10628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C., & Keller, G. (1998). A common precursor for hematopoietic and endothelial cells. Development, 125, 725–732.

    CAS  PubMed  Google Scholar 

  • Christensen, J. L., Wright, D. E., Wagers, A. J., & Weissman, I. L. (2004). Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biology, 2, E75.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cumano, A., Ferraz, J. C., Klaine, M., Di Santo, J. P., & Godin, I. (2001). Intraembryonic, but not yolk sac hematopoietic precursors, isolated before circulation, provide long-term multilineage reconstitution. Immunity, 15, 477–485.

    Article  CAS  PubMed  Google Scholar 

  • De Bruijn, M. F., Speck, N. A., Peeters, M. C., & Dzierzak, E. (2000). Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. The EMBO Journal, 19, 2465–2474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dieterlen-Lievre, F. (1975). On the origin of haemopoietic stem cells in the avian embryo: An experimental approach. Journal of Embryology and Experimental Morphology, 33, 607–619.

    CAS  PubMed  Google Scholar 

  • Eilken, H. M., Nishikawa, S., & Schroeder, T. (2009). Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature, 457, 896–900.

    Article  CAS  PubMed  Google Scholar 

  • Eliades, A., Wareing, S., Marinopoulou, E., Fadlullah, M. Z., Patel, R., Grabarek, J. B., et al. (2016). The hemogenic competence of endothelial progenitors is restricted by Runx1 silencing during embryonic development. Cell Reports, 15, 2185–2199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ema, H., & Nakauchi, H. (2000). Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood, 95, 2284–2288.

    CAS  PubMed  Google Scholar 

  • Ema, M., Faloon, P., Zhang, W. J., Hirashima, M., Reid, T., Stanford, W. L., et al. (2003). Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes & Development, 17, 380–393.

    Article  CAS  Google Scholar 

  • Ferkowicz, M. J., & Yoder, M. C. (2005). Blood island formation: Longstanding observations and modern interpretations. Experimental Hematology, 33, 1041–1047.

    Article  PubMed  Google Scholar 

  • Frame, J. M., Fegan, K. H., Conway, S. J., Mcgrath, K. E., & Palis, J. (2015). Definitive hematopoiesis in the yolk sac emerges from Wnt-responsive hemogenic endothelium independently of circulation and arterial identity. Stem Cells, 34, 431–444.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fraser, S. T., Ogawa, M., Yokomizo, T., Ito, Y., & Nishikawa, S. (2003). Putative intermediate precursor between hematogenic endothelial cells and blood cells in the developing embryo. Development, Growth & Differentiation, 45, 63–75.

    Article  CAS  Google Scholar 

  • Fujita, Y., Nishimura, M., Taniwaki, M., Abe, T., & Okuda, T. (2001). Identification of an alternatively spliced form of the mouse AML1/RUNX1 gene transcript AML1c and its expression in early hematopoietic development. Biochemical and Biophysical Research Communications, 281, 1248–1255.

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C., & Orkin, S. H. (1996). Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proceedings of the National Academy of Sciences of the United States of America, 93, 12355–12358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gekas, C., Dieterlen-Lievre, F., Orkin, S. H., & Mikkola, H. K. (2005). The placenta is a niche for hematopoietic stem cells. Developmental Cell, 8, 365–375.

    Article  CAS  PubMed  Google Scholar 

  • Ghozi, M. C., Bernstein, Y., Negreanu, V., Levanon, D., & Groner, Y. (1996). Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions. Proceedings of the National Academy of Sciences of the United States of America, 93, 1935–1940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginhaux, F., & Jung, S. (2014). Monocytes and macrophages: Developmental pathways and tissue homeostasis. Nature Reviews Immunology, 14, 392–404.

    Google Scholar 

  • Gordon-Keylock, S., Sobiesiak, M., Rybtsov, S., Moore, K., & Medvinsky, A. (2013). Mouse extraembryonic arterial vessels harbor precursors capable of maturing into definitive HSCs. Blood, 122, 2338–2345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Growney, J. D., Shigematsu, H., Li, Z., Lee, B. H., Adelsperger, J., Rowan, R., et al. (2005). Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood, 106, 494–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haar, J. L., & Ackerman, G. A. (1971). A phase and electron microscopic study of vasculogenesis and erythropoiesis in the yolk sac of the mouse. The Anatomical Record, 170, 199–223.

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto, K., Fujimoto, T., Shimoda, Y., Huang, X., Sakamoto, H., & OGAWA, M. (2007). Distinct hemogenic potential of endothelial cells and CD41+ cells in mouse embryos. Development, Growth & Differentiation, 49, 287–300.

    Article  Google Scholar 

  • Hoogenkamp, M., Lichtinger, M., Krysinska, H., Lancrin, C., Clarke, D., Williamson, A., et al. (2009). Early chromatin unfolding by RUNX1: A molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. Blood, 114, 299–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, G., Zhang, P., Hirai, H., Elf, S., Yan, X., Chen, Z., et al. (2008). PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nature Genetics, 40, 51–60.

    Article  CAS  PubMed  Google Scholar 

  • Iacovino, M., Chong, D., Szatmari, I., Hartweck, L., Rux, D., Caprioli, A., et al. (2011). HoxA3 is an apical regulator of haemogenic endothelium. Nature Cell Biology, 13, 72–78.

    Article  CAS  PubMed  Google Scholar 

  • Ichikawa, M., Asai, T., Saito, T., Seo, S., Yamazaki, I., Yamagata, T., et al. (2004). AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nature Medicine, 10, 299–304.

    Article  CAS  PubMed  Google Scholar 

  • Iizuka, K., Yokomizo, T., Watanabe, N., Tanaka, Y., Osata, M., Takaku, T., et al. (2016). Lack of phenotypical and morphological evidences of endothelial to hematopoietic transition in the murine embryonic head during hematopoietic stem cell emergence. PLoS One, 11, e0156427.

    Google Scholar 

  • Ivanovs, A., Rybtsov, S., Welch, L., Anderson, R. A., Turner, M. L., & Medvinsky, A. (2011). Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. The Journal of Experimental Medicine, 208, 2417–2427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaffredo, T., Bollerot, K., Sugiyama, D., Gautier, R., & Drevon, C. (2005). Tracing the hemangioblast during embryogenesis: Developmental relationships between endothelial and hematopoietic cells. The International Journal of Developmental Biology, 49, 269–277.

    Article  CAS  PubMed  Google Scholar 

  • Kalev-Zylinska, M. L., Horsfield, J. A., Flores, M. V., Postlethwait, J. H., Vitas, M. R., Baas, A. M., et al. (2002). Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1-CBF2T1 transgene advances a model for studies of leukemogenesis. Development, 129, 2015–2030.

    CAS  PubMed  Google Scholar 

  • Kataoka, H., Hayashi, M., Nakagawa, R., Tanaka, Y., Izumi, N., Nishikawa, S., et al. (2011). Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm. Blood, 118, 6975–6986.

    Article  CAS  PubMed  Google Scholar 

  • Kieusseian, A., Brunet De LA Grange, P., Burlen-Defranoux, O., Godin, I., & Cumano, A. (2012). Immature hematopoietic stem cells undergo maturation in the fetal liver. Development, 139, 3521–3530.

    Article  CAS  PubMed  Google Scholar 

  • Kingsley, P. D., Malik, J., Fantauzzo, K. A., & Palis, J. (2004). Yolk sac-derived primitive erythroblasts enucleate during mammalian embryogenesis. Blood, 104, 19–25.

    Article  CAS  PubMed  Google Scholar 

  • Kissa, K., & Herbomel, P. (2010). Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature, 464, 112–115.

    Article  CAS  PubMed  Google Scholar 

  • Kissa, K., Murayama, E., Zapata, A., Cortes, A., Perret, E., Machu, C., & Herbomel, P. (2008). Live imaging of emerging hematopoietic stem cells and early thymus colonization. Blood, 111, 1147–1156.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi, A., Senzaki, K., Ozaki, S., Yoshikawa, M., & Shiga, T. (2012). Runx1 promotes neuronal differentiation in dorsal root ganglion. Molecular and Cellular Neurosciences, 49, 23–31.

    Article  CAS  PubMed  Google Scholar 

  • Lacaud, G., Gore, L., Kennedy, M., Kouskoff, V., Kingsley, P., Hogan, C., et al. (2002). Runx1 is essential for hematopoietic commitment at the hemangioblast stage of development in vitro. Blood, 100, 458–466.

    Article  CAS  PubMed  Google Scholar 

  • Lacaud, G., Kouskoff, V., Trumble, A., Schwantz, S., & Keller, G. (2004). Haploinsufficiency of Runx1 results in the acceleration of mesodermal development and hemangioblast specification upon in vitro differentiation of ES cells. Blood, 103, 886–889.

    Article  CAS  PubMed  Google Scholar 

  • Lancrin, C., Sroczynska, P., Stephenson, C., Allen, T., Kouskoff, V., & Lacaud, G. (2009). The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature, 457, 892–895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lancrin, C., Mazan, M., Stefanska, M., Patel, R., Lichtinger, M., Costa, G., et al. (2012). GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment. Blood, 120, 314–322.

    Article  CAS  PubMed  Google Scholar 

  • Lawson, K. A., Meneses, J. J., & Pedersen, R. A. (1991). Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development, 113, 891–911.

    CAS  PubMed  Google Scholar 

  • Levanon, D., & Groner, Y. (2004). Structure and regulated expression of mammalian RUNX genes. Oncogene, 23, 4211–4219.

    Article  CAS  PubMed  Google Scholar 

  • Levanon, D., Bernstein, Y., Negreanu, V., Ghozi, M. C., Bar-Am, I., Aloya, R., et al. (1996). A large variety of alternatively spliced and differentially expressed mRNAs are encoded by the human acute myeloid leukemia gene AML1. DNA and Cell Biology, 15, 175–185.

    Article  CAS  PubMed  Google Scholar 

  • Levanon, D., Brenner, O., Negreanu, V., Bettoun, D., Woolf, E., Eilam, R., et al. (2001a). Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Mechanisms of Development, 109, 413–417.

    Article  CAS  PubMed  Google Scholar 

  • Levanon, D., Glusman, G., Bangsow, T., Ben-Asher, E., Male, D. A., Avidan, N., et al. (2001b). Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. Gene, 262, 23–33.

    Article  CAS  PubMed  Google Scholar 

  • Li, W., Ferkowicz, M. J., Johnson, S. A., Shelley, W. C., & Yoder, M. C. (2005). Endothelial cells in the early murine yolk sac give rise to CD41-expressing hematopoietic cells. Stem Cells and Development, 14, 44–54.

    Article  PubMed  Google Scholar 

  • Li, Z., Chen, M. J., Stacy, T., & Speck, N. A. (2006). Runx1 function in hematopoiesis is required in cells that express Tek. Blood, 107, 106–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Z., Lan, Y., He, W., Chen, D., Wang, J., Zhou, F., et al. (2012). Mouse embryonic head as a site for hematopoietic stem cell development. Cell Stem Cell, 11, 663–675.

    Article  CAS  PubMed  Google Scholar 

  • Li, Y., Esain, V., Teng, L., Xu, J., Kwan, W., Frost, I. M., et al. (2014). Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes & Development, 28, 2597–2612.

    Article  CAS  Google Scholar 

  • Li, Z., Vink, C. S., Mariani, S. A., & Dzierzak, E. (2016). Subregional localization and characterization of Ly6aGFP-expressing hematopoietic cells in the mouse embryonic head. Developmental Biology, 416, 34–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liakhovitskaia, A., Gribi, R., Stamateris, E., Villain, G., Jaffredo, T., Wilkie, R., et al. (2009). Restoration of Runx1 expression in the Tie2 cell compartment rescues definitive hematopoietic stem cells and extends life of Runx1 knockout animals until birth. Stem Cells, 27, 1616–1624.

    Article  CAS  PubMed  Google Scholar 

  • Liakhovitskaia, A., Lana-Elola, E., Stamateris, E., Rice, D. P., Van ‘T Hof, R. J., & Medvinsky, A. (2010). The essential requirement for Runx1 in the development of the sternum. Developmental Biology, 340, 539–546.

    Article  CAS  PubMed  Google Scholar 

  • Liakhovitskaia, A., Rybtsov, S., Smith, T., Batsivari, A., Rybtsova, N., Rode, C., et al. (2014). Runx1 is required for progression of CD41+ embryonic precursors into HSCs but not prior to this. Development, 141, 3319–3323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lichtinger, M., Ingram, R., Hannah, R., Müller, D., Clarke, D., Assi, S. A., et al. (2012). RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis. The EMBO Journal, 31, 4318–4333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lie-A-Ling, M., Marinopoulou, E., Li, Y., Patel, R., Stefanska, M., Bonifer, C., et al. (2014). RUNX1 positively regulates a cell adhesion and migration program in murine hemogenic endothelium prior to blood emergence. Blood, 124, e11–e20.

    Article  CAS  PubMed  Google Scholar 

  • Lorsbach, R. B., Moore, J., Ang, S. O., Sun, W., Lenny, N., & Downing, J. R. (2004). Role of Runx1 in adult hematopoiesis: Analysis of Runx1-IRES-GFP knock-in mice reveals differential lineage expression. Blood, 103, 2522–2529.

    Article  CAS  PubMed  Google Scholar 

  • Martinez, M., Hinojosa, M., Trombly, D., Morin, V., Stein, J., Stein, G., et al. (2016). Transcriptional Auto-Regulation of RUNX1 P1 Promoter. PloS One, 11, e0149119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mcgrath, K. E., Frame, J. M., Fegan, K. H., Bowen, J. R., Conway, S. J., Catherman, S. C., et al. (2015). Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo. Cell Reports, 11, 1892–1904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medvinsky, A., & Dzierzak, E. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell, 86, 897–906.

    Article  CAS  PubMed  Google Scholar 

  • Mikkola, H. K., Fujiwara, Y., Schlaeger, T. M., Traver, D., & Orkin, S. H. (2003). Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood, 101, 508–516.

    Article  CAS  PubMed  Google Scholar 

  • Moore, M. A., & Metcalf, D. (1970). Ontogeny of the haemopoietic system: Yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. British Journal of Haematology, 18, 279–296.

    Article  CAS  PubMed  Google Scholar 

  • Mukouyama, Y., Chiba, N., Hara, T., Okada, H., Ito, Y., Kanamaru, R., et al. (2000). The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Developmental Biology, 220, 27–36.

    Article  CAS  PubMed  Google Scholar 

  • Müller, A. M., Medvinsky, A., Strouboulis, J., Grosveld, F., & Dzierzak, E. (1994). Development of hematopoietic stem cell activity in the mouse embryo. Immunity, 1, 291–301.

    Article  PubMed  Google Scholar 

  • Murayama, E., Kissa, K., Zapata, A., Mordelet, E., Briolat, V., Lin, H. F., et al. (2006). Tracing hematopoietic precursor migration to successive hematopoietic organs during zebrafish development. Immunity, 25, 963–975.

    Article  CAS  PubMed  Google Scholar 

  • Murray, P. (1932). The development in vitro of the blood of the early chick embryo. London: Proceedings of the Royal Society.

    Google Scholar 

  • Nakano, H., Liu, X., Arshi, A., Nakashima, Y., Van Handel, B., Sasidharan, R., et al. (2013). Haemogenic endocardium contributes to transient definitive haematopoiesis. Nature Communications, 4, 1564.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ng, C. E., Yokomizo, T., Yamashita, N., Cirovic, B., Jin, H., Wen, Z., et al. (2010). A Runx1 intronic enhancer marks hemogenic endothelial cells and hematopoietic stem cells. Stem Cells, 28, 1869–1881.

    Article  CAS  PubMed  Google Scholar 

  • Niki, M., Okada, H., Takano, H., Kuno, J., Tani, K., Hibino, H., et al. (1997). Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor. Proceedings of the National Academy of Sciences of the United States of America, 94, 5697–5702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolan, D. J., Ginsberg, M., Israely, E., Palikuqi, B., Poulos, M. G., James, D., et al. (2013). Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Developmental Cell, 26, 204–219.

    Article  CAS  PubMed  Google Scholar 

  • North, T., Gu, T. L., Stacy, T., Wang, Q., Howard, L., Binder, M., et al. (1999). Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development, 126, 2563–2575.

    CAS  PubMed  Google Scholar 

  • North, T. E., De Bruijn, M. F., Stacy, T., Talebian, L., Lind, E., Robin, C., et al. (2002). Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity, 16, 661–672.

    Article  CAS  PubMed  Google Scholar 

  • North, T. E., Stacy, T., Matheny, C. J., Speck, N. A., & De Bruijn, M. F. (2004). Runx1 is expressed in adult mouse hematopoietic stem cells and differentiating myeloid and lymphoid cells, but not in maturing erythroid cells. Stem Cells, 22, 158–168.

    Article  CAS  PubMed  Google Scholar 

  • Nottingham, W. T., Jarratt, A., Burgess, M., Speck, C. L., Cheng, J. F., Prabhakar, S., et al. (2007). Runx1-mediated hematopoietic stem-cell emergence is controlled by a Gata/Ets/SCL-regulated enhancer. Blood, 110, 4188–4197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okuda, T., Van Deursen, J., Hiebert, S. W., Grosveld, G., & Downing, J. R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell, 84, 321–330.

    Article  CAS  PubMed  Google Scholar 

  • Padron-Barthe, L., Temino, S., Villa Del Campo, C., Carramolino, L., Isern, J., & Torres, M. (2014). Clonal analysis identifies hemogenic endothelium as the source of the blood-endothelial common lineage in the mouse embryo. Blood, 124, 2523–2532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palis, J. (2014). Primitive and definitive erythropoiesis in mammals. Frontiers in Physiology, 5, 3.

    Article  PubMed  PubMed Central  Google Scholar 

  • Palis, J., Robertson, S., Kennedy, M., Wall, C., & Keller, G. (1999). Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development, 126, 5073–5084.

    CAS  PubMed  Google Scholar 

  • Potts, K. S., Sargeant, T. J., Markham, J. F., Shi, W., Biben, C., Josefsson, E. C., et al. (2014). A lineage of diploid platelet-forming cells precedes polyploid megakaryocyte formation in the mouse embryo. Blood, 124, 2725–2729.

    Article  CAS  PubMed  Google Scholar 

  • Pozner, A., Goldenberg, D., Negreanu, V., Le, S. Y., Elroy-Stein, O., Levanon, D., & Groner, Y. (2000). Transcription-coupled translation control of AML1/RUNX1 is mediated by cap- and internal ribosome entry site-dependent mechanisms. Molecular and Cellular Biology, 20, 2297–2307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pozner, A., Lotem, J., Xiao, C., Goldenberg, D., Brenner, O., Negreanu, V., et al. (2007). Developmentally regulated promoter-switch transcriptionally controls Runx1 function during embryonic hematopoiesis. BMC Developmental Biology, 7, 84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Putz, G., Rosner, A., Nuesslein, I., Schmitz, N., & Buchholz, F. (2006). AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene, 25, 929–939.

    Article  CAS  PubMed  Google Scholar 

  • Rennert, J., Coffman, J. A., Mushegian, A. R., & Robertson, A. J. (2003). The evolution of Runx genes I. A comparative study of sequences from phylogenetically diverse model organisms. BMC Evolutionary Biology, 3, 4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rhodes, K. E., Gekas, C., Wang, Y., Lux, C. T., Francis, C. S., Chan, D. N., et al. (2008). The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell, 2, 252–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rybtsov, S., Sobiesiak, M., Taoudi, S., Souilhol, C., Senserrich, J., Liakhovitskaia, A., et al. (2011). Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. The Journal of Experimental Medicine, 208, 1305–1315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rybtsov, S., Ivanovs, A., Zhao, S., & Medvinsky, A. (2016). Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver. Development, 143, 1284–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sabin, F. R. (1920). Studies on the origin of blood-vessels and of red blood-corpuscles as seen in the living blastoderm of chicks during the second day of incubation. Contributions to Embryology, 30 x 24 cm, 213–262.

    Google Scholar 

  • Sandler, V. M., Lis, R., Liu, Y., Kedem, A., James, D., Elemento, O., et al. (2014). Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature, 511, 312–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sasaki, K., Yagi, H., Bronson, R. T., Tominaga, K., Matsunashi, T., Deguchi, K., et al. (1996). Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proceedings of the National Academy of Sciences of the United States of America, 93, 12359–12363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuette, J., Wang, H., Antoniou, S., Jarrat, A., Wilson, N. K., Riepsaame, J., et al. (2016). An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability. eLife, 5, e11469.

    Google Scholar 

  • Sroczynska, P., Lancrin, C., Kouskoff, V., & Lacaud, G. (2009). The differential activities of Runx1 promoters define milestones during embryonic hematopoiesis. Blood, 114, 5279–5289.

    Article  CAS  PubMed  Google Scholar 

  • Swiers, G., Baumann, C., O’rourke, J., Giannoulatou, E., Taylor, S., Joshi, A., et al. (2013a). Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. Nature Communications, 4, 2924.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Swiers, G., Rode, C., Azzoni, E., & De Bruijn, M. F. (2013b). A short history of hemogenic endothelium. Blood Cells, Molecules & Diseases, 51, 206–212.

    Article  CAS  Google Scholar 

  • Takakura, N., Watanabe, T., Suenobu, S., Yamada, Y., Noda, T., Ito, Y., et al. (2000). A role for hematopoietic stem cells in promoting angiogenesis. Cell, 102, 199–209.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka, Y., Sanchez, V., Takata, N., Yokomizo, T., Yamanaka, Y., Kataoka, H., et al. (2014). Circulation-independent differentiation pathway from extraembryonic mesoderm toward hematopoietic stem cells via hemogenic angioblasts. Cell Reports, 8, 31–39.

    Article  CAS  PubMed  Google Scholar 

  • Taoudi, S., Gonneau, C., Moore, K., Sheridan, J. M., Blackburn, C. C., Taylor, E., & Medvinsky, A. (2008). Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell, 3, 99–108.

    Article  CAS  PubMed  Google Scholar 

  • Telfer, J. C., & Rothenberg, E. V. (2001). Expression and function of a stem cell promoter for the murine CBFalpha2 gene: Distinct roles and regulation in natural killer and T cell development. Developmental Biology, 229, 363–382.

    Article  CAS  PubMed  Google Scholar 

  • Thambyrajah, R., Mazan, M., Patel, R., Moignard, V., Stefanska, M., Marinopoulou, E., et al. (2016). GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1. Nature Cell Biology, 18, 21–32.

    Article  CAS  PubMed  Google Scholar 

  • Tober, J., Koniski, A., Mcgrath, K. E., Vemishetti, R., Emerson, R., De Mesy-Bentley, K. K., et al. (2007). The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood, 109, 1433–1441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tober, J., Yzaguirre, A. D., Piwarzyk, E., & Speck, N. A. (2013). Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells. Development, 140, 3765–3776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tracey, W. D., Pepling, M. E., Horb, M. E., Thomsen, G. H., & Gergen, J. P. (1998). A Xenopus homologue of aml-1 reveals unexpected patterning mechanisms leading to the formation of embryonic blood. Development, 125, 1371–1380.

    CAS  PubMed  Google Scholar 

  • Ueno, H., & Weissman, I. L. (2006). Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Developmental Cell, 11, 519–533.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A. H., & Speck, N. A. (1996a). Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America, 93, 3444–3449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Q., Stacy, T., Miller, J. D., Lewis, A. F., Gu, T. L., Huang, X., et al. (1996b). The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell, 87, 697–708.

    Article  CAS  PubMed  Google Scholar 

  • Wareing, S., Eliades, A., Lacaud, G., & Kouskoff, V. (2012). ETV2 expression marks blood and endothelium precursors, including hemogenic endothelium, at the onset of blood development. Developmental Dynamics, 241, 1454–1464.

    Article  CAS  PubMed  Google Scholar 

  • Witzenbichler, B., Maisonpierre, P. C., Jones, P., Yancopoulos, G. D., & Isner, J. M. (1998). Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. The Journal of Biological Chemistry, 273, 18514–18521.

    Article  CAS  PubMed  Google Scholar 

  • Xu, M. J., Matsuoka, S., Yang, F. C., Ebihara, Y., Manabe, A., Tanaka, R., et al. (2001). Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac. Blood, 97, 2016–2022.

    Article  CAS  Google Scholar 

  • Yoder, M. C. (2014). Inducing definitive hematopoiesis in a dish. Nature Biotechnology, 32, 539–541.

    Article  CAS  PubMed  Google Scholar 

  • Yokomizo, T., & Dzierzak, E. (2010). Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos. Development, 137, 3651–3661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokomizo, T., Ogawa, M., Osato, M., Kanno, T., Yoshida, H., Fujimoto, T., et al. (2001). Requirement of Runx1/AML1/PEBP2alphaB for the generation of haematopoietic cells from endothelial cells. Genes to Cells, 6, 13–23.

    Article  CAS  PubMed  Google Scholar 

  • Yokomizo, T., Hasegawa, K., Ishitobi, H., Osato, M., Ema, M., Ito, Y., et al. (2008). Runx1 is involved in primitive erythropoiesis in the mouse. Blood, 111, 4075–4080.

    Article  CAS  PubMed  Google Scholar 

  • Yoshimoto, M., Montecino-Rodriguez, E., Ferkowicz, M. J., Porayette, P., Shelley, W. C., Conway, S. J., et al. (2011). Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proceedings of the National Academy of Sciences of the United States of America, 108, 1468–1473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshimoto, M., Porayette, P., Glosson, N. L., Conway, S. J., Carlesso, N., Cardoso, A. A., et al. (2012). Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence. Blood, 119, 5706–5714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, M., Mazor, T., Huang, H., Huang, H. T., Kathrein, K. L., Woo, A. J., et al. (2012). Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Molecular Cell, 45, 330–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yzaguirre, A. D., & Speck, N. A. (2016). Insights into blood cell formation from hemogenic endothelium in lesser-known anatomic sites. Developmental Dynamics, 245, 1011–1028.

    Article  PubMed  Google Scholar 

  • Zambidis, E. T., Peault, B., Park, T. S., Bunz, F., & Civin, C. I. (2005). Hematopoietic differentiation of human embryonic stem cells progresses through sequential hematoendothelial, primitive, and definitive stages resembling human yolk sac development. Blood, 106, 860–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeigler, B. M., Sugiyama, D., Chen, M., Guo, Y., Downs, K. M., & Speck, N. A. (2006). The allantois and chorion, when isolated before circulation or chorio-allantoic fusion, have hematopoietic potential. Development, 133, 4183–4192.

    Article  CAS  PubMed  Google Scholar 

  • Zhen, F., Lan, Y., Yan, B., Zhang, W., & Wen, Z. (2013). Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms. Development, 140, 3977–3985.

    Article  CAS  PubMed  Google Scholar 

  • Zovein, A. C., Hofmann, J. J., Lynch, M., French, W. J., Turlo, K. A., Yang, Y., et al. (2008). Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell, 3, 625–636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19103, USA

    Amanda D. Yzaguirre & Nancy A. Speck

  2. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, OX3 9DS, UK

    Marella F. T. R. de Bruijn

Authors
  1. Amanda D. Yzaguirre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marella F. T. R. de Bruijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nancy A. Speck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy A. Speck .

Editor information

Editors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Yoram Groner

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Yoshiaki Ito

  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Paul Liu

  4. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom

    James C. Neil

  5. Department of Cell and Development Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Nancy A. Speck

  6. Mayo Clinic, Rochester, Minnesota, USA

    Andre van Wijnen

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Yzaguirre, A.D., de Bruijn, M.F.T.R., Speck, N.A. (2017). The Role of Runx1 in Embryonic Blood Cell Formation. In: Groner, Y., Ito, Y., Liu, P., Neil, J., Speck, N., van Wijnen, A. (eds) RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology, vol 962. Springer, Singapore. https://doi.org/10.1007/978-981-10-3233-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation