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A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
Please always quote using this 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.…
Author: | 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 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Pathologisches Institut |
Language: | English |
Parent Title (English): | Nature Communications |
Year of Completion: | 2016 |
Volume: | 7 |
Article Number: | 11841 |
Source: | Nature Communications 2016, 7:11841. DOI: 10.1038/ncomms11841 |
DOI: | https://doi.org/10.1038/ncomms11841 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | acute lymphocytic leukaemia; lymphocyte differentiation; transcription factors |
Release Date: | 2021/03/16 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |