ArticleNature2007
Calcineurin sets the bandwidth for discrimination of signals during thymocyte development.
Article in Nature, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 66 citations in OpenAlex.
- The thymus road to a T cell: migration, selection, and atrophy.Frontiers in immunology · 2024Review
- Single-cell multiomic analysis of thymocyte development reveals drivers of CD4Nature immunology · 2023Article
- CaInternational journal of molecular sciences · 2023Article
- T cell self-reactivity during thymic development dictates the timing of positive selection.eLife · 2021Article
- ASIC1a induces synovial inflammation via the CaTheranostics · 2020Article
- NFAT primes the human RORC locus for RORγt expression in CD4Nature communications · 2019Article
- The ESCRT protein CHMP5 escorts αβ T cells through positive selection.Cellular & molecular immunology · 2018Article
- NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection.Nature communications · 2017Article
- Post-translational control of T cell development by the ESCRT protein CHMP5.Nature immunology · 2017Article
- Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.Nature communications · 2017Article
- Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants.Oncotarget · 2016Article
- Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.BioMed research international · 2015Review
- Calcium and calcineurin-NFAT signaling regulate granulocyte-monocyte progenitor cell cycle via Flt3-L.Stem cells (Dayton, Ohio) · 2014Article
- N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca²⁺ signaling.Nature immunology · 2014Article
- Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia.Nature communications · 2014Article
- A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction.Immunology · 2014Article
- Diacylglycerol metabolism attenuates T-cell receptor signaling and alters thymocyte differentiation.Cell death & disease · 2013Article
- Thymic regulatory T cell development: role of signalling pathways and transcription factors.Clinical & developmental immunology · 2013Review
- A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.Nature immunology · 2012Article
- Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling.Nature immunology · 2012Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.