Calcineurin sets the bandwidth for discrimination of signals during thymocyte development

Elena MacFarlane, Monte M. Winslow, Kirsten Canté-Barrett, Amy N. Radermacher, Lena Ho, Lisa McGinnis, Brian Iritani, Joel R. Neilson, Gerald R. Crabtree

Research output: Contribution to journalArticle

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 αβ 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.

Original languageEnglish (US)
Pages (from-to)731-735
Number of pages5
JournalNature
Volume450
Issue number7170
DOIs
StatePublished - Nov 29 2007
Externally publishedYes

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Calcineurin
Thymocytes
Extracellular Signal-Regulated MAP Kinases
NFATC Transcription Factors
T-Cell Antigen Receptor
Apoptosis
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Hypersensitivity
Peptides
Population

ASJC Scopus subject areas

  • General

Cite this

MacFarlane, E., Winslow, M. M., Canté-Barrett, K., Radermacher, A. N., Ho, L., McGinnis, L., ... Crabtree, G. R. (2007). Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature, 450(7170), 731-735. https://doi.org/10.1038/nature06305

Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. / MacFarlane, Elena; Winslow, Monte M.; Canté-Barrett, Kirsten; Radermacher, Amy N.; Ho, Lena; McGinnis, Lisa; Iritani, Brian; Neilson, Joel R.; Crabtree, Gerald R.

In: Nature, Vol. 450, No. 7170, 29.11.2007, p. 731-735.

Research output: Contribution to journalArticle

MacFarlane, E, Winslow, MM, Canté-Barrett, K, Radermacher, AN, Ho, L, McGinnis, L, Iritani, B, Neilson, JR & Crabtree, GR 2007, 'Calcineurin sets the bandwidth for discrimination of signals during thymocyte development', Nature, vol. 450, no. 7170, pp. 731-735. https://doi.org/10.1038/nature06305
MacFarlane E, Winslow MM, Canté-Barrett K, Radermacher AN, Ho L, McGinnis L et al. Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature. 2007 Nov 29;450(7170):731-735. https://doi.org/10.1038/nature06305
MacFarlane, Elena ; Winslow, Monte M. ; Canté-Barrett, Kirsten ; Radermacher, Amy N. ; Ho, Lena ; McGinnis, Lisa ; Iritani, Brian ; Neilson, Joel R. ; Crabtree, Gerald R. / Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. In: Nature. 2007 ; Vol. 450, No. 7170. pp. 731-735.
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