Tcf-1 in early lymphoid development (115.14)

Abstract

Abstract In hematopoiesis, the transcriptional networks governing lineage choice from pluripotent progenitors to mature lymphoid cells remain poorly understood. Although some key factors associated with the specification and commitment of T cells have been described, the functional roles of key regulators in orchestrating these developmental programs remain unclear. Using a loss-of-function model, we established the importance of T-cell factor 1 (Tcf-1), a T-cell specific mediator of Wnt signaling, as a gatekeeper of T-cell fate. We show that Tcf-1 is directly activated by Notch signals. Activation of Notch signaling in uncommitted precursors by the thymic stroma is known to initiate the T-cell differentiation program, and we show that Tcf-1 is one regulator first induced in these precursors. Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor (ETP) stage, and this requirement is cell intrinsic and Wnt independent. The global expression profile of Tcf-1 deficient progenitors indicates that basic processes of DNA metabolism are downregulated in its absence, and the blocked T-cell progenitors die by apoptosis. While Tcf-1 is dispensable for the development of bone marrow (BM) progenitors and their migration through the blood, we present evidence for a novel role for Tcf-1 in early BM natural killer (NK) development. Our data thus demonstrate multiple roles for Tcf-1 in the roadmap of lymphoid development.