A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development.
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 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.
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Stefan
S
Klein-Hessling
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Ronald
R
Rudolf
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Khalid
K
Muhammad
Department of Pathology, Institute of Neuropathology, University Clinic Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany.
Klaus-Peter
KP
Knobeloch
Institute de Génétique Moléculaire de Montpellier (IGMM), UMR5535 CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
Muhammad Ahmad
MA
Maqbool
Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Pierre
P
Cauchy
Institute de Génétique Moléculaire de Montpellier (IGMM), UMR5535 CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
Jean-Christophe
JC
Andrau
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Andris
0000-0001-7396-5629
A
Avots
Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
Claudio
C
Talora
Department of Gastroenterology II, University of Goettingen, Robert Koch Strasse 40, 37075 Goettingen, Germany.
Volker
V
Ellenrieder
Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
Isabella
I
Screpanti
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Edgar
E
Serfling
Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
Amiya Kumar
AK
Patra
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002470:Cell Survival; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D000071656:Receptor, Notch3 / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C499373:Notch3 protein, mouse; D020033:Protein Isoforms; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell