Calcineurin/NFAT signalling inhibits myeloid haematopoiesis.
Bottom Line: Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment.Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis.In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development.
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.Show MeSH
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Mentions: Given that NFAT1 is expressed in stem cells more strongly than other NFAT proteins (Kiani et al, 2004) and that Flt3-L is a key growth factor in early myeloid development, we initially analysed total expression of NFAT1 protein in control-tdTomato and VIVIT-eGFP expressing HSC, both in the steady-state and in response to Flt3-L stimulation, to determine whether Flt3-L influences NFAT expression. By Western blot analysis, NFAT1 expression could be detected in untreated HSC lines, and stimulation with Flt3-L for 48 h moderately up-regulated expression levels (Fig 1A). Notably, NFAT1 expression was far lower than was observed in PMA-stimulated T cells (Fig 1A; positive control) and in un-stimulated T cells (unpublished observations). Up-regulation of NFAT1 protein in response to Flt3-L was also detected at the mRNA level (Fig 1B). In further experiments, it was possible to demonstrate enhanced expression of NFAT1 and NFAT2 mRNA in BM cells treated with Flt3-L. Sorted lineage negative BM cells (lin−; CD3e−, B220−, CD19− CD11b−, Gr-1−, TER-119−, NK1.1− and CD127−) were used to exclude any contribution from differentiated cells and lymphoid progenitors (Fig 1C).
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.