A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development

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

doi:10.1038/ncomms11841

A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development

Nat Commun. 2016 Jun 17:7:11841. doi: 10.1038/ncomms11841.

Affiliations

¹ Department of Molecular Pathology, Institute for Pathology, University of Wuerzburg, Josef-Schneider Strasse 2, 97080 Wuerzburg, Germany.
² Department of Pathology, Institute of Neuropathology, University Clinic Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany.
³ Institute de Génétique Moléculaire de Montpellier (IGMM), UMR5535 CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
⁴ Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
⁵ Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
⁶ Department of Gastroenterology II, University of Goettingen, Robert Koch Strasse 40, 37075 Goettingen, Germany.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / cytology
B-Lymphocytes / immunology
Cell Differentiation
Cell Lineage / genetics
Cell Lineage / immunology
Cell Survival
Gene Expression Regulation, Developmental / immunology
Lymphopenia / genetics
Lymphopenia / immunology*
Lymphopenia / pathology
Mice
Mice, Knockout
NFATC Transcription Factors / genetics
NFATC Transcription Factors / immunology*
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
Promoter Regions, Genetic
Protein Isoforms / genetics
Protein Isoforms / immunology
Receptor, Notch3 / genetics
Receptor, Notch3 / immunology*
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Signal Transduction
T-Lymphocytes / cytology
T-Lymphocytes / immunology*
Thymocytes / cytology
Thymocytes / immunology*
Thymus Gland / cytology
Thymus Gland / immunology

Substances

NFATC Transcription Factors
Nfatc1 protein, mouse
Notch3 protein, mouse
Protein Isoforms
Receptor, Notch3
Receptors, Antigen, T-Cell