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

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 Nfatc1? expression, preTCR-positive thymocytes express both Nfatc1? and P1 promoter-derived Nfatc1? transcripts. Inducing NFATc1? activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1? 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.

SUBMITTER: Klein-Hessling S 

PROVIDER: S-EPMC4915031 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature