| First Author | Hirano K | Year | 2015 |
| Journal | Eur J Immunol | Volume | 45 |
| Issue | 8 | Pages | 2252-62 |
| PubMed ID | 25976373 | Mgi Jnum | J:229751 |
| Mgi Id | MGI:5754425 | Doi | 10.1002/eji.201445123 |
| Citation | Hirano K, et al. (2015) Delta-like 4-mediated Notch signaling is required for early T-cell development in a three-dimensional thymic structure. Eur J Immunol 45(8):2252-62 |
| abstractText | 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 alphabeta T or gammadelta T/NK cell lineage, did not differentiate into the alphabeta 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 alphabeta 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 alphabeta 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. |
