Abstract
Notch1 is involved in directing cell fate decisions in a variety of developmental scenarios. Extending previous experiments in mice, we generated transgenic rats expressing the intracellular domain of Notch1 in the thymus. Importantly, this leads to sustained expression of the pre-TCR throughout thymocyte development, accompanied by a reduction of alphabetaTCR complexes. In addition, re-expression of RAG-1 and RAG-2 in TCRbeta(+) cells is impaired, and the Valpha repertoire is altered. Consequently, thymocytes in transgenic rats do not undergo positive selection and largely fail to progress to the single positive stage. According to our model, the previously reported effects of Notch1 on the CD4/CD8 cell fate decision may be explained by a differential sensitivity of the two lineages toward altered TCR signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Apoptosis / genetics
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Apoptosis / immunology
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Cell Differentiation / genetics*
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Cell Differentiation / immunology*
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Cell Lineage / genetics
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Cell Lineage / immunology
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Female
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Intracellular Fluid / immunology*
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Intracellular Fluid / metabolism*
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Lymphopenia / genetics
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Lymphopenia / immunology
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Lymphopenia / pathology
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / physiology
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Mice
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Protein Structure, Tertiary / genetics
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Rats
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Rats, Inbred Lew
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Receptor, Notch1
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Receptors, Antigen, T-Cell, alpha-beta / antagonists & inhibitors
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Receptors, Antigen, T-Cell, alpha-beta / biosynthesis*
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Receptors, Antigen, T-Cell, alpha-beta / physiology
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology*
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Thymus Gland / pathology
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Transcription Factors / genetics*
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Transcription Factors / physiology
Substances
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DNA-Binding Proteins
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Homeodomain Proteins
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Membrane Glycoproteins
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Notch1 protein, mouse
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Notch1 protein, rat
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Rag2 protein, mouse
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Receptor, Notch1
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Cell Surface
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Transcription Factors
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V(D)J recombination activating protein 2
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pre-T cell receptor alpha
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RAG-1 protein