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Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions

(2011) BLOOD. 117(17). p.4449-4459
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Abstract
Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe-mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.
Keywords
B-CELL, EPITHELIAL-CELLS, STEM-CELLS, T-CELLS, TCR-ALPHA-BETA, IN-VITRO, IMMUNE-SYSTEM, PROGENITOR CELLS, DIFFERENTIATION, EXPRESSION

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Chicago
Van de Walle, Inge, Greet De Smet, Martina Gärtner, Magda De Smedt, Els Waegemans, Bart Vandekerckhove, Georges Leclercq, et al. 2011. “Jagged2 Acts as a Delta-like Notch Ligand During Early Hematopoietic Cell Fate Decisions.” Blood 117 (17): 4449–4459.
APA
Van de Walle, I., De Smet, G., Gärtner, M., De Smedt, M., Waegemans, E., Vandekerckhove, B., Leclercq, G., et al. (2011). Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. BLOOD, 117(17), 4449–4459.
Vancouver
1.
Van de Walle I, De Smet G, Gärtner M, De Smedt M, Waegemans E, Vandekerckhove B, et al. Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. BLOOD. 2011;117(17):4449–59.
MLA
Van de Walle, Inge, Greet De Smet, Martina Gärtner, et al. “Jagged2 Acts as a Delta-like Notch Ligand During Early Hematopoietic Cell Fate Decisions.” BLOOD 117.17 (2011): 4449–4459. Print.
@article{1235372,
  abstract     = {Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe-mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.},
  author       = {Van de Walle, Inge and De Smet, Greet and G{\"a}rtner, Martina and De Smedt, Magda and Waegemans, Els and Vandekerckhove, Bart and Leclercq, Georges and Plum, Jean and Aster, Jon C and Bernstein, Irwin D and Guidos, Cynthia J and Kyewski, Bruno and Taghon, Tom},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {B-CELL,EPITHELIAL-CELLS,STEM-CELLS,T-CELLS,TCR-ALPHA-BETA,IN-VITRO,IMMUNE-SYSTEM,PROGENITOR CELLS,DIFFERENTIATION,EXPRESSION},
  language     = {eng},
  number       = {17},
  pages        = {4449--4459},
  title        = {Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions},
  url          = {http://dx.doi.org/10.1182/blood-2010-06-290049},
  volume       = {117},
  year         = {2011},
}

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