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The Developmentally Regulated Expression of Twisted Gastrulation Reveals a Role for Bone Morphogenetic Proteins in the Control of T Cell Development

Daniel Graf^1,3, Suran Nethisinghe¹, Donald B. Palmer², Amanda G. Fisher¹ and Matthias Merkenschlager¹

¹ Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre
² Department of Immunology, Imperial College of Medicine, London W12 0NN, United Kingdom
³ Institute of Immunology Biomedical Sciences Research Centre‘Al Fleming’, 166 72 Vari, Greece

Address correspondence to M. Merkenschlager, Lymphocyte Development Group, Imperial College of Medicine, Hammersmith Campus, Du Cane Rd., London W12 0NN, UK. Phone: 44-208-383-8236; Fax: 44-208-383-8338; E-mail: matthias.merkenschlager{at}csc.mrc.ac.uk

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.

Key Words: BMP4 • Twisted gastrulation • thymocyte development • chordin • morphogen

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