GATA-3 in precursor commitment to the T lineage

Summary

Principal Investigator: ELLEN ROTHENBERG
Abstract: Commitment of hematopoietic precursors to the T lineage occurs after entry of the cells into the thymus and the onset of expression of a diverse set of T-lineage associated genes. To date, no specific regulatory factor has been identified that carries out T lineage commitment in a way analogous to the role of Pax5 in B lineage cells. In recent work, however, our group has shown two regulatory transitions in T-cell precursors that parallel lineage commitment: the shutoff of PU.1 expression and a marked increase in tolerance for high levels of GATA-3 activity. Although GATA-3 is essential for T-cell development, its effects are dose- and stage-dependent, and high-level expression at an early stage causes a severe block to entry into the T-cell pathway. The pronounced discontinuity between the responses of precursors forced to overexpress GATA- 3 earlier or later in T-cell development suggests that a major regulatory shift in target gene accessibility or target gene function occurs at the time of lineage commitment. This proposal is to determine the nature of this regulatory shift. We have already identified an initial set of target genes that appear to be perturbed by GATA-3 in immature thymocytes, and a mutant form of GATA-3 that retains the severity of the early effects with minimal inhibition after T-lineage commitment. The research we propose to do builds on these initial findings to dissect the mechanisms through which GATA-3 exerts its different actions so that an aspect of T-lineage commitment can be defined at a molecular level. The specific aims are: 1. Comparison of GATA-3 target genes in pre- and post-commitment T-cell precursors 2. Definition of mechanistic requirements for GATA-3 perturbation of T-cell development 3. Attempted rescue of GATA-3 overexpression effects by cotransduction with targets of specific repression
Funding Period: 2003-01-01 - 2008-12-31
more information: NIH RePORT

Top Publications

  1. pmc T cell lineage commitment: identity and renunciation
    Ellen V Rothenberg
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    J Immunol 186:6649-55. 2011
  2. pmc A gene regulatory network armature for T lymphocyte specification
    Constantin Georgescu
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 105:20100-5. 2008
  3. ncbi Molecular mechanisms that control mouse and human TCR-alphabeta and TCR-gammadelta T cell development
    Tom Taghon
    Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital, Ghent University, De Pintelaan 185, 4 Blok A, 9000, Ghent, Belgium
    Semin Immunopathol 30:383-98. 2008
  4. pmc Competition and collaboration: GATA-3, PU.1, and Notch signaling in early T-cell fate determination
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Semin Immunol 20:236-46. 2008
  5. pmc Launching the T-cell-lineage developmental programme
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, California 91125, USA
    Nat Rev Immunol 8:9-21. 2008
  6. pmc Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3
    Tom Taghon
    Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, 9000 Ghent, Belgium
    Nat Immunol 8:845-55. 2007
  7. ncbi Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Immunity 26:690-702. 2007
  8. ncbi Molecular dissection of prethymic progenitor entry into the T lymphocyte developmental pathway
    C Chace Tydell
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    J Immunol 179:421-38. 2007
  9. ncbi Regulatory factors for initial T lymphocyte lineage specification
    Ellen V Rothenberg
    Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    Curr Opin Hematol 14:322-9. 2007
  10. pmc Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
    Christopher B Franco
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 103:11993-8. 2006

Scientific Experts

  • ELLEN ROTHENBERG
  • Tom Taghon
  • Elizabeth Sharon David-Fung
  • Mary A Yui
  • Constantin Georgescu
  • Deirdre D Scripture-Adams
  • C Chace Tydell
  • Christopher B Franco
  • Rochelle A Diamond
  • Mark A Zarnegar
  • William J R Longabaugh
  • Hamid Bolouri
  • Jonathan E Moore
  • Lee Rowen
  • Hua Wang
  • Marissa Morales
  • Angela H Weiss
  • Stephanie L Adams
  • Irina Proekt

Detail Information

Publications14

  1. pmc T cell lineage commitment: identity and renunciation
    Ellen V Rothenberg
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    J Immunol 186:6649-55. 2011
    ..This regulatory mosaic has notable implications for the hierarchy of relationships linking T lymphocytes to other hematopoietic fates...
  2. pmc A gene regulatory network armature for T lymphocyte specification
    Constantin Georgescu
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 105:20100-5. 2008
    ..1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression...
  3. ncbi Molecular mechanisms that control mouse and human TCR-alphabeta and TCR-gammadelta T cell development
    Tom Taghon
    Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital, Ghent University, De Pintelaan 185, 4 Blok A, 9000, Ghent, Belgium
    Semin Immunopathol 30:383-98. 2008
    ..We discuss the differences in cellular events between the alphabeta and gammadelta developmental pathways and try to correlate these with a corresponding complexity of the molecular mechanisms that support them...
  4. pmc Competition and collaboration: GATA-3, PU.1, and Notch signaling in early T-cell fate determination
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Semin Immunol 20:236-46. 2008
    ..1, and Notch-Delta signals, whose counterbalance appears to be essential for T-cell specification...
  5. pmc Launching the T-cell-lineage developmental programme
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, California 91125, USA
    Nat Rev Immunol 8:9-21. 2008
    ....
  6. pmc Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3
    Tom Taghon
    Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, 9000 Ghent, Belgium
    Nat Immunol 8:845-55. 2007
    ..Our results suggest a close relationship between the pro-T cell and mast cell programs and a previously unknown function for Notch in T lineage fidelity...
  7. ncbi Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals
    Ellen V Rothenberg
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Immunity 26:690-702. 2007
    ..An additional mechanism, still not fully defined, is required just prior to T cell receptor-mediated selection to end plasticity and make T lineage commitment irreversible...
  8. ncbi Molecular dissection of prethymic progenitor entry into the T lymphocyte developmental pathway
    C Chace Tydell
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    J Immunol 179:421-38. 2007
    ..Bcl11b was uniquely T lineage restricted and induced by Notch/Delta signaling specifically upon entry into the T lineage differentiation pathway...
  9. ncbi Regulatory factors for initial T lymphocyte lineage specification
    Ellen V Rothenberg
    Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    Curr Opin Hematol 14:322-9. 2007
    ..1, growth factor independence (Gfi)-1, T cell factor (TCF)-1, and Runx factors and their interactions with the Notch pathway to promote T cell development...
  10. pmc Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
    Christopher B Franco
    Division of Biology 156 29, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 103:11993-8. 2006
    ..The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment...
  11. pmc Progression of regulatory gene expression states in fetal and adult pro-T-cell development
    Elizabeth Sharon David-Fung
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    Immunol Rev 209:212-36. 2006
    ..The results also reveal global differences in regulatory alterations triggered by the first T-cell receptor-dependent selection events in fetal and adult thymopoiesis...
  12. ncbi Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus
    Tom Taghon
    Division of Biology, MC 156 29, California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA
    Immunity 24:53-64. 2006
    ..Our results also reveal differences in Notch/Delta dependence at the earliest stages of divergence between developing alphabeta and gammadelta T-lineage cells...
  13. pmc Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling
    Tom N Taghon
    Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    Genes Dev 19:965-78. 2005
    ....
  14. ncbi Molecular genetics of T cell development
    Ellen V Rothenberg
    Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    Annu Rev Immunol 23:601-49. 2005
    ....