Abstract
Bone morphogenetic protein (BMP)2 and BMP4 are involved in the development of many tissues. In this study, we show that BMP2/4 signaling is involved in thymocyte development. Our data suggest that termination of BMP2/4 signaling is necessary for differentiation of CD44(+)CD25(-)CD4(-)CD8(-) double negative (DN) cells along the T cell lineage. BMP2 and BMP4 are produced by the thymic stroma and the requisite BMP receptor molecules (BMPR-1A, BMPR-1B, BMPR-II), and signal transduction molecules (Smad-1, -5, -8, and -4) are expressed by DN thymocytes. BMP4 inhibits thymocyte proliferation, enhances thymocyte survival, and arrests thymocyte differentiation at the CD44(+)CD25(-) DN stage, before T cell lineage commitment. Neutralization of endogenous BMP2 and BMP4 by treatment with the antagonist Noggin promotes and accelerates thymocyte differentiation, increasing the expression of CD2 and the proportion of CD44(-)CD25(-) DN cells and CD4(+)CD8(+) double-positive cells. Our study suggests that the BMP2/4 pathway may function in thymic homeostasis by regulating T cell lineage commitment and differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / biosynthesis
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Activin Receptors, Type I / genetics
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Adjuvants, Immunologic / pharmacology
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Adjuvants, Immunologic / physiology
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Animals
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Protein Receptors, Type I
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Bone Morphogenetic Proteins / antagonists & inhibitors
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Bone Morphogenetic Proteins / physiology*
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Carrier Proteins
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Cells, Cultured
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Dose-Response Relationship, Immunologic
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Fetus
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Gene Expression Regulation / immunology
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Genes, T-Cell Receptor beta / genetics
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Genes, T-Cell Receptor delta / genetics
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Growth Inhibitors / physiology
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Hyaluronan Receptors / biosynthesis
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Hyaluronan Receptors / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Organ Culture Techniques
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Protein Serine-Threonine Kinases*
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Proteins / pharmacology
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Receptors, Growth Factor*
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Interleukin-2 / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / cytology*
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T-Lymphocytes / metabolism
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Thymus Gland / cytology*
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Thymus Gland / metabolism
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Transforming Growth Factor beta*
Substances
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Adjuvants, Immunologic
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Bmp2 protein, mouse
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins
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Carrier Proteins
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Growth Inhibitors
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Hyaluronan Receptors
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Proteins
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Receptors, Growth Factor
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Receptors, Interleukin-2
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Recombinant Fusion Proteins
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Transforming Growth Factor beta
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noggin protein
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Bone Morphogenetic Protein Receptors, Type I