A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-172974
- NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.…
Autor(en): | Stefan Klein-Hessling, Ronald Rudolf, Khalid Muhammad, Klaus-Peter Knobeloch, Muhammad Ahmad Maqbool, Pierre Cauchy, Jean-Christophe Andrau, Andris Avots, Claudio Talora, Volker Ellenrieder, Isabella Screpanti, Edgar Serfling, Amiya Kumar Patra |
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URN: | urn:nbn:de:bvb:20-opus-172974 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Pathologisches Institut |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Nature Communications |
Erscheinungsjahr: | 2016 |
Band / Jahrgang: | 7 |
Aufsatznummer: | 11841 |
Originalveröffentlichung / Quelle: | Nature Communications 2016, 7:11841. DOI: 10.1038/ncomms11841 |
DOI: | https://doi.org/10.1038/ncomms11841 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | acute lymphocytic leukaemia; lymphocyte differentiation; transcription factors |
Datum der Freischaltung: | 16.03.2021 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |