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Ternary complex factor SAP-1 is required for Erk-mediated thymocyte positive selection.
Patrick S Costello1, Robert H Nicolas, Yasuyuki Watanabe
1Transcription Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Fields, London WC2A 3PX, UK.
Nature Immunology
|February 11, 2004
Summary
SAP-1 (also known as Elk4) is crucial for T cell development. This study shows SAP-1 links Erk signaling to essential transcriptional events for thymocyte positive selection, impacting T cell numbers.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- Thymocyte selection and differentiation depend on extracellular signal-regulated kinase (Erk) signaling.
- The specific transcription factor substrates of Erk within thymocytes remain largely unknown.
- Understanding these substrates is key to deciphering T cell development pathways.
Purpose of the Study:
- To investigate the function of the Erk-regulated transcription factor SAP-1 (Elk4) in thymocyte development.
- To determine if SAP-1 plays a role in linking Erk signaling to T cell receptor-induced gene expression.
- To elucidate SAP-1's contribution to thymocyte positive and negative selection processes.
Main Methods:
- Characterization of thymocyte development in SAP-1-deficient mice.
- Analysis of T cell receptor-induced activation of SAP-1 target genes (e.g., Egr1) in thymocytes.
- Assessment of thymocyte positive and negative selection using T cell receptor transgenes.
Main Results:
- Early thymocyte development proceeded normally in SAP-1-deficient mice.
- Reduced numbers of single-positive thymocytes and peripheral T cells were observed, indicating a T cell-autonomous defect.
- T cell receptor-induced activation of SAP-1 target genes was impaired in double-positive thymocytes, despite normal Erk activation.
- Positive selection was significantly reduced (80-90%) in SAP-1-deficient mice, with a moderate defect in heterozygous mice.
- Negative selection remained unaffected.
Conclusions:
- SAP-1 (Elk4) is a critical transcription factor in thymocyte development.
- SAP-1 directly connects extracellular signal-regulated kinase (Erk) signaling to the transcriptional requirements for thymocyte positive selection.
- Defects in SAP-1 function lead to impaired T cell development and reduced T cell populations.