Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 50, Pages 20060-20065Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110230108
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Funding
- National Institutes of Health [R01AI059676, F31 AI830542, R01CA133379, R01CA105129, R21CA141399, R01CA149655]
- Leukemia and Lymphoma Society
- American Cancer Society [RSG0806801]
- Irma T. Hirschl Charitable Trust
- Dana Foundation
- Mallinckrodt Foundation
- Gabrielle's Angels Foundation
- Alex's Lemonade Stand Foundation
- Helen L. and Martin S. Kimmel Center
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Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA-binding protein T-cell factor 1 (Tcf-1), a T-cell-specific mediator of Wnt signaling. However, the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate and show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor stage. The global expression profile of Tcf-1-deficient progenitors indicates that basic processes of DNA metabolism are down-regulated in its absence, and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the road-map of T-cell development.
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