Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation.
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.
Hager-Theodorides
Ariadne L
AL
Department of Biological Sciences, Imperial College of Science Technology and Medicine, London SW7 2AZ, UK.
Outram
Susan V
SV
Shah
Divya K
DK
Sacedon
Rosa
R
Shrimpton
Rachel E
RE
Vicente
Angeles
A
Varas
Alberto
A
Crompton
Tessa
T
D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005333:Fetus; D005786:Gene Expression Regulation / Q000276:immunology; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D019676:Genes, T-Cell Receptor delta / Q000235:genetics; D006131:Growth Inhibitors / Q000502:physiology; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000494:pharmacology; D017978:Receptors, Growth Factor; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D030201:Activin Receptors, Type I; D000276:Adjuvants, Immunologic; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D006131:Growth Inhibitors; D018960:Hyaluronan Receptors; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017978:Receptors, Growth Factor; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse