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: Microarray analysis of gene expression in BM cells was performed at 12, 24 and 48 h after Flt3-L stimulation, and in fully differentiated Flt3-L-treated DC cultivated in the presence or absence of CsA. Differential gene expression in CsA-treated BM cells began 48 h after stimulation (Fig S5A of Supporting Information). At this time point, 35 transcripts were up-regulated and 131 transcripts were decreased in Flt3-L-stimulated BM cells treated with CsA. On day 11 of the culture, fully differentiated Flt3-L/CsA-treated DC displayed 110 up-regulated transcripts and 571 down-regulated transcripts compared with untreated controls (Fig S5B of Supporting Information). Ingenuity Systems Pathway Analysis of these transcripts showed enrichment for genes involved in ‘Haematological System Development and Function’, and ‘Cellular Growth and Proliferation’ (Fig S5C of Supporting Information). Some of the differentially expressed genes in these subsets encode known crucial regulators of myeloid development and cell cycle (Fig 6A and B and Table 1). Genes important in DC development (Ikzf3, Spib and Stat4) were down-regulated, while genes responsible for cell cycle progression (Etv1, Epas1, Nupr1, Nfia and Atf5) were up-regulated. Critically, down-regulated transcription of the cell cycle repressor Cdkn1a (p21) was also observed (Fig 6A and Table 1), and was confirmed by qPCR (Fig 6A). Furthermore, increased levels of Cdk4 mRNA at 11 days time-point were detected in CsA treated cells (Fig 6A).
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.