FADD regulates thymocyte development at the β-selection checkpoint by modulating Notch signaling

• Published in: Cell death & disease Vol. 5; no. 6; p. e1273
• Main Authors: Zhang, X, Dong, X, Wang, H, Li, J, Yang, B, Zhang, J, Hua, Z-C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 05.06.2014
• Subjects: Animals; Cell Survival - physiology; Fas-Associated Death Domain Protein - genetics; Fas-Associated Death Domain Protein - metabolism; Gene Expression Regulation - physiology; Mice; Mice, Knockout; Original; Receptor, Notch1 - biosynthesis; Receptor, Notch1 - genetics; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - physiology; Thymocytes - cytology; Thymocytes - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.198

Non-apoptotic functions of Fas-associated protein with death domain (FADD) have been implicated in T lineage lymphocytes, but the nature of FADD-dependent non-apoptotic mechanism in early T-cell development has not been completely elucidated. In this study, we show that tissue-specific deletion of FADD in immature (CD44(-)CD25(+)) thymocytes results in severe perturbation of αβ lineage development. Meanwhile, loss of FADD signaling at a later (CD44(-)CD25(-)) developmental stage does not affect subsequent T-cell development. Collectively, our work presents that FADD deficiency induces failed survival in double-negative 4 (DN4) cells, while pre-T-cell receptor (TCR) signal remains intact. In addition, Notch signaling is positive regulated on DN4 and double-positive thymocytes in T-cell-specific FADD-knockout mice, which express higher levels of a subset of Notch-target genes, including Hes1, Deltex1 and CD25. Moreover, a transcriptional repressor of Notch1, NKAP is downregulated coupled with the loss of FADD in thymocytes and is found to associate with FADD. These data suggest that as a death receptor, FADD is also required for cell survival in β-selection as a regulator of Notch1 expression.