T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling

K Germar, M Dose, T Konstantinou… - Proceedings of the …, 2011 - National Acad Sciences
K Germar, M Dose, T Konstantinou, J Zhang, H Wang, C Lobry, KL Arnett, SC Blacklow
Proceedings of the National Academy of Sciences, 2011National Acad Sciences
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 …
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 roadmap of T-cell development.
National Acad Sciences