Advanced search
1 file | 660.74 KB Add to list

Notch3 activation is sufficient but not required for inducing human T-lineage specification

Els Waegemans (UGent) , Inge Van de Walle (UGent) , Jelle De Medts (UGent) , Magda De Smedt (UGent) , Tessa Kerre (UGent) , Bart Vandekerckhove (UGent) , Georges Leclercq (UGent) , Tao Wang, Jean Plum (UGent) and Tom Taghon (UGent)
(2014) JOURNAL OF IMMUNOLOGY. 193(12). p.5997-6004
Author
Organization
Abstract
Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34(+) hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors.
Keywords
HUMAN LUNG CANCERS, HEMATOPOIETIC STEM-CELLS, TCR-ALPHA-BETA, DELTA-LIKE 4, SIGNALING PATHWAY, TRANSCRIPTION FACTOR, B-CELL, THYMUS, PROGENITORS, EXPRESSION

Downloads

  • Notch3 specification accepted biblio.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 660.74 KB

Citation

Please use this url to cite or link to this publication:

MLA
Waegemans, Els et al. “Notch3 Activation Is Sufficient but Not Required for Inducing Human T-lineage Specification.” JOURNAL OF IMMUNOLOGY 193.12 (2014): 5997–6004. Print.
APA
Waegemans, E., Van de Walle, I., De Medts, J., De Smedt, M., Kerre, T., Vandekerckhove, B., Leclercq, G., et al. (2014). Notch3 activation is sufficient but not required for inducing human T-lineage specification. JOURNAL OF IMMUNOLOGY, 193(12), 5997–6004.
Chicago author-date
Waegemans, Els, Inge Van de Walle, Jelle De Medts, Magda De Smedt, Tessa Kerre, Bart Vandekerckhove, Georges Leclercq, Tao Wang, Jean Plum, and Tom Taghon. 2014. “Notch3 Activation Is Sufficient but Not Required for Inducing Human T-lineage Specification.” Journal of Immunology 193 (12): 5997–6004.
Chicago author-date (all authors)
Waegemans, Els, Inge Van de Walle, Jelle De Medts, Magda De Smedt, Tessa Kerre, Bart Vandekerckhove, Georges Leclercq, Tao Wang, Jean Plum, and Tom Taghon. 2014. “Notch3 Activation Is Sufficient but Not Required for Inducing Human T-lineage Specification.” Journal of Immunology 193 (12): 5997–6004.
Vancouver
1.
Waegemans E, Van de Walle I, De Medts J, De Smedt M, Kerre T, Vandekerckhove B, et al. Notch3 activation is sufficient but not required for inducing human T-lineage specification. JOURNAL OF IMMUNOLOGY. 2014;193(12):5997–6004.
IEEE
[1]
E. Waegemans et al., “Notch3 activation is sufficient but not required for inducing human T-lineage specification,” JOURNAL OF IMMUNOLOGY, vol. 193, no. 12, pp. 5997–6004, 2014.
@article{5801548,
  abstract     = {Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34(+) hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors.},
  author       = {Waegemans, Els and Van de Walle, Inge and De Medts, Jelle and De Smedt, Magda and Kerre, Tessa and Vandekerckhove, Bart and Leclercq, Georges and Wang, Tao and Plum, Jean and Taghon, Tom},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  keywords     = {HUMAN LUNG CANCERS,HEMATOPOIETIC STEM-CELLS,TCR-ALPHA-BETA,DELTA-LIKE 4,SIGNALING PATHWAY,TRANSCRIPTION FACTOR,B-CELL,THYMUS,PROGENITORS,EXPRESSION},
  language     = {eng},
  number       = {12},
  pages        = {5997--6004},
  title        = {Notch3 activation is sufficient but not required for inducing human T-lineage specification},
  url          = {http://dx.doi.org/10.4049/jimmunol.1400764},
  volume       = {193},
  year         = {2014},
}

Altmetric
View in Altmetric
Web of Science
Times cited: