The developmentally regulated expression of Twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development.
The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and their differentiation to the CD4(+)CD8(+) double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4(+) or CD8(+) single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals.
Graf
Daniel
D
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College of Medicine, London W12 0NN, United Kingdom.
Nethisinghe
Suran
S
Palmer
Donald B
DB
Fisher
Amanda G
AG
Merkenschlager
Matthias
M
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D029721:Drosophila Proteins; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C090223:TSG protein, Drosophila; D016212:Transforming Growth Factor beta; C054234:chordin