Abstract
Stem cell factor (SCF), the ligand for the c-kit receptor, is essential for the production of red blood cells during development and stress erythropoiesis. SCF promotes erythroblast proliferation and survival, while delaying erythroid differentiation through mechanisms that are largely unknown. In cultures of primary human differentiating erythroblasts, we found that SCF induces an increase in the expression of Notch2, a member of the Notch family implicated in the control of cell growth and differentiation. Functional inhibition of either Notch or its ligand Jagged1 inhibited the effects of SCF on erythroid cell expansion. SCF also induced the expression of Hes-1 and GATA-2, which may contribute to transduce Notch2 signals in response to SCF. Transduction of primary erythroid precursors with a dominant-negative Notch2 mutant inhibited both basal and SCF-mediated erythroblast expansion, and counteracted the effects of SCF on erythroblast differentiation. These findings provide a clue to understand the effects of increased proliferation and delayed differentiation elicited by SCF on the erythroid compartment and indicate Notch2 as a new player in the regulation of red cell differentiation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- SCF:
-
stem cell factor
- NICD:
-
Notch intracellular domain
- HSC:
-
hematopoietic stem cells
- GpA:
-
Glycophorin A
- Notch2 Intra:
-
intracellular Notch2 mutant
- Notch2 Extra:
-
extracellular Notch2 mutant
- Notch2 FL:
-
full-length Notch2
- GFP:
-
green fluorescent protein
- 7-AAD:
-
7-amino-actinomycin D
- HPC:
-
hematopoietic progenitor cell
- RV:
-
retroviral vector
- C/G:
-
copies per genome
- BASO:
-
basophilic erythroblasts
- POLY:
-
polychromatophilic erythroblasts
- ORTHO:
-
orthochromatic erythroblasts
- MFI:
-
mean fluorescence intensity
- JAG1:
-
Jagged1
References
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 1990; 63: 213–224.
Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A . The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988; 335: 88–89.
Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1990; 63: 225–233.
Geissler EN, Ryan MA, Housman DE . The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 1988; 55: 185–192.
Muta K, Krantz SB, Bondurant MC, Dai CH . Stem cell factor retards differentiation of normal human erythroid progenitor cells while stimulating proliferation. Blood 1995; 86: 572–580.
Endo T, Odb A, Satoh I, Haseyama Y, Nishio M, Koizumi K et al. Stem cell factor protects c-kit+ human primary erythroid cells from apoptosis. Exp Hematol 2001; 29: 833–841.
Zeuner A, Pedini F, Signore M, Testa U, Pelosi E, Peschle C et al. Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins. Blood 2003; 102: 87–93.
Kapur R, Chandra S, Cooper R, McCarthy J, Williams DA . Role of p38 and ERK MAP kinase in proliferation of erythroid progenitors in response to stimulation by soluble and membrane isoforms of stem cell factor. Blood 2002; 100: 1287–1293.
Fortini ME . Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 2009; 16: 633–647.
Ohishi K, Katayama N, Shiku H, Varnum-Finney B, Bernstein ID . Notch signalling in hematopoiesis. Semin Cell Dev Biol 2003; 14: 143–150.
Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2008; 2: 356–366.
Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, MacDonald HR et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999; 10: 547–558.
Schwanbeck R, Schroeder T, Henning K, Kohlhof H, Rieber N, Erfurth ML et al. Notch signaling in embryonic and adult myelopoiesis. Cells Tissues Organs 2008; 188: 91–102.
Tachikawa Y, Matsushima T, Abe Y, Sakano S, Yamamoto M, Nishimura J et al. Pivotal role of Notch signaling in regulation of erythroid maturation and proliferation. Eur J Haematol 2006; 77: 273–281.
Ishiko E, Matsumura I, Ezoe S, Gale K, Ishiko J, Satoh Y et al. Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1. J Biol Chem 2005; 280: 4929–4939.
Bigas A, Martin DI, Milner LA . Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol 1998; 18: 2324–2333.
Walker L, Lynch M, Silverman S, Fraser J, Boulter J, Weinmaster G et al. The Notch/Jagged pathway inhibits proliferation of human hematopoietic progenitors in vitro. Stem Cells 1999; 17: 162–171.
Ohishi K, Varnum-Finney B, Flowers D, Anasetti C, Myerson D, Bernstein ID . Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1. Blood 2000; 95: 2847–2854.
Mercher T, Cornejo MG, Sears C, Kindler T, Moore SA, Maillard I et al. Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell 2008; 3: 314–326.
Henning K, Schroeder T, Schwanbeck R, Rieber N, Bresnick EH, Just U . mNotch1 signaling and erythropoietin cooperate in erythroid differentiation of multipotent progenitor cells and upregulate beta-globin. Exp Hematol 2007; 35: 1321–1332.
Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 2000; 405: 966–970.
Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y . Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 1999; 126: 3415–3424.
Robert-Moreno A, Espinosa L, Sanchez MJ, de la Pompa JL, Bigas A . The notch pathway positively regulates programmed cell death during erythroid differentiation. Leukemia 2007; 21: 1496–1503.
Zhou L, Li LW, Yan Q, Petryniak B, Man Y, Su C et al. Notch-dependent control of myelopoiesis is regulated by fucosylation. Blood 2008; 112: 308–319.
Zeuner A, Pedini F, Signore M, Ruscio G, Messina C, Tafuri A et al. Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. Blood 2006; 107: 3495–3502.
Zeuner A, Pedini F, Francescangeli F, Signore M, Girelli G, Tafuri A et al. Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells. Blood 2009; 113: 1522–1525.
Rebay I, Fehon RG, Artavanis-Tsakonas S . Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 1993; 74: 319–329.
Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD . Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 1996; 16: 952–959.
Kopan R, Ilagan MX . The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137: 216–233.
Mancini SJ, Mantei N, Dumortier A, Suter U, MacDonald HR, Radtke F . Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 2005; 105: 2340–2342.
Perry JM, Harandi OF, Paulson RF . BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood 2007; 109: 4494–4502.
Tamir A, Petrocelli T, Stetler K, Chu W, Howard J, Croix BS et al. Stem cell factor inhibits erythroid differentiation by modulating the activity of G1-cyclin-dependent kinase complexes: a role for p27 in erythroid differentiation coupled G1 arrest. Cell Growth Differ 2000; 11: 269–277.
Cheng X, Huber TL, Chen VC, Gadue P, Keller GM . Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Development 2008; 135: 3447–3458.
Kim YW, Koo BK, Jeong HW, Yoon MJ, Song R, Shin J et al. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood 2008; 112: 4628–4638.
Qyang Y, Chambers SM, Wang P, Xia X, Chen X, Goodell MA et al. Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. Biochemistry 2004; 43: 5352–5359.
Das AV, James J, Zhao X, Rahnenfuhrer J, Ahmad I . Identification of c-Kit receptor as a regulator of adult neural stem cells in the mammalian eye: interactions with Notch signaling. Dev Biol 2004; 273: 87–105.
Schouwey K, Delmas V, Larue L, Zimber-Strobl U, Strobl LJ, Radtke F et al. Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner. Dev Dyn 2007; 236: 282–289.
Grignani F, Kinsella T, Mencarelli A, Valtieri M, Riganelli D, Lanfrancone L et al. High-efficiency gene transfer and selection of human hematopoietic progenitor cells with a hybrid EBV/retroviral vector expressing the green fluorescence protein. Cancer Res 1998; 58: 14–19.
Acknowledgements
We thank Stefano Guida for excellent technical assistance, Giuseppe Loreto for graphics, Gualtiero Mariani and Mauro Biffoni for flow cytometry, Agnese D’Angiò for cell purification, and Ferdinando Pucci for DNA analysis. This work was supported by the Italian Association for Cancer Research (AIRC). MS is the recipient of an Italy-USA Collaborative Program fellowship. This work is dedicated to the memory of Elisa Santolini, our beloved colleague.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by G Cossu
Supplementary Information accompanies the paper on Cell Death and Differentiation website
Supplementary information
Rights and permissions
About this article
Cite this article
Zeuner, A., Francescangeli, F., Signore, M. et al. The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell Death Differ 18, 371–380 (2011). https://doi.org/10.1038/cdd.2010.110
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cdd.2010.110
Keywords
This article is cited by
-
Increased expression of RUNX3 inhibits normal human myeloid development
Leukemia (2022)
-
Notch2 signal is required for the maintenance of canine hemangiosarcoma cancer stem cell-like cells
BMC Veterinary Research (2018)
-
Mesenchymal stem cell-mediated Notch2 activation overcomes radiation-induced injury of the hematopoietic system
Scientific Reports (2018)
-
The role of GATA2 in lethal prostate cancer aggressiveness
Nature Reviews Urology (2017)
-
Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver
Cell Death & Differentiation (2015)
