Delta-like 4-mediated Notch signaling is required for early T-cell development in a three-dimensional thymic structure
- PMID: 25976373
- DOI: 10.1002/eji.201445123
Delta-like 4-mediated Notch signaling is required for early T-cell development in a three-dimensional thymic structure
Abstract
Delta-like 4 (Dll4)-mediated Notch signaling is critical for specifying T-cell fate, but how Dll4-mediated Notch signaling actually contributes to T-cell development in the thymus remains unclear. To explore this mechanism in the thymic three-dimensional structure, we performed fetal thymus organ culture using Dll4-deficient mice. DN1a/b+DN2mt cells, which had not yet committed to either the αβ T or γδ T/NK cell lineage, did not differentiate into the αβ T-cell lineage in Dll4-deficient thymus despite the lack of cell fate conversion into other lineages. However, DN3 cells efficiently differentiated into a later developmental stage of αβ T cells, the double-positive (DP) stage, although the proliferation was significantly impaired during the differentiation process. These findings suggest that the requirement for Notch signaling differs between the earliest and pre-TCR-bearing precursors and that continued Notch signaling is required for proper differentiation with active proliferation of αβ T lineage cells. Furthermore, we showed that Notch signaling increased the c-Myc expression in DN3 cells in the thymus and that its overexpression rescued the proliferation and differentiation of DN3 cells in the Dll4-null thymus. Therefore, c-Myc plays a central role in the transition from stage DN3 to DP as a downstream target of Notch signaling.
Keywords: Dll4; Notch signal; T-cell development; Thymus; c-Myc.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Similar articles
-
Ongoing Dll4-Notch signaling is required for T-cell homeostasis in the adult thymus.Eur J Immunol. 2011 Aug;41(8):2207-16. doi: 10.1002/eji.201041343. Epub 2011 Jul 4. Eur J Immunol. 2011. PMID: 21598246
-
Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength.J Exp Med. 2013 Apr 8;210(4):683-97. doi: 10.1084/jem.20121798. Epub 2013 Mar 25. J Exp Med. 2013. PMID: 23530123 Free PMC article. Clinical Trial.
-
DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells.Eur J Immunol. 2013 Nov;43(11):2845-53. doi: 10.1002/eji.201343527. Epub 2013 Aug 25. Eur J Immunol. 2013. PMID: 23881845
-
Gammadelta T cell development--having the strength to get there.Curr Opin Immunol. 2005 Apr;17(2):108-15. doi: 10.1016/j.coi.2005.01.009. Curr Opin Immunol. 2005. PMID: 15766668 Review.
-
Decision checkpoints in the thymus.Nat Immunol. 2010 Aug;11(8):666-73. doi: 10.1038/ni.1887. Epub 2010 Jul 20. Nat Immunol. 2010. PMID: 20644572 Free PMC article. Review.
Cited by
-
Can a Proper T-Cell Development Occur in an Altered Thymic Epithelium? Lessons From EphB-Deficient Thymi.Front Endocrinol (Lausanne). 2018 Apr 3;9:135. doi: 10.3389/fendo.2018.00135. eCollection 2018. Front Endocrinol (Lausanne). 2018. PMID: 29666605 Free PMC article.
-
EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells.Organogenesis. 2017 Oct 2;13(4):192-211. doi: 10.1080/15476278.2017.1389368. Organogenesis. 2017. PMID: 29027839 Free PMC article.
-
The RANKL-RANK Axis: A Bone to Thymus Round Trip.Front Immunol. 2019 Mar 29;10:629. doi: 10.3389/fimmu.2019.00629. eCollection 2019. Front Immunol. 2019. PMID: 30984193 Free PMC article. Review.
-
Notch2 complements Notch1 to mediate inductive signaling that initiates early T cell development.J Cell Biol. 2020 Oct 5;219(10):e202005093. doi: 10.1083/jcb.202005093. J Cell Biol. 2020. PMID: 32756905 Free PMC article.
-
Two distinct Notch signals, Delta-like 4/Notch1 and Jagged-1/Notch2, antagonistically regulate chemical hepatocarcinogenesis in mice.Commun Biol. 2022 Jan 21;5(1):85. doi: 10.1038/s42003-022-03013-8. Commun Biol. 2022. PMID: 35064244 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
