title: FADD regulates thymocyte development at the β-selection checkpoint by modulating Notch signaling.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China [2] Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target-Pharma Laboratories Inc., Changzhou, China.
authors.forename: Z-C
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell