A critical role for TCF-1 in T-lineage specification and differentiation', Nature 476(7358): 63–68

The vertebrate thymus provides an inductive environment for T-cell development. Within the thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential hematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that transcription factor, T-cell factor 1 (TCF-1), is a critical regulator in T-cell specification. TCF-1 is highly expressed in the earliest thymic progenitors, and its expression is upregulated by Notch signals. Most importantly, when TCF-1 is forcibly expressed in BM progenitors, it drives the development of T-lineage cells in the absence of T-inductive Notch1 signals. Further characterization of these TCF-1-induced cells revealed expression of many T-lineage genes, including T-cell specific transcription factors Gata3, Bcl11b, and components of the T-cell receptor. Our data suggest a model where Notch signals induce TCF-1, and TCF-1 in turn imprints the T-cell fate by upregulating expression of T-cell essential genes. Within the thymus, Notch1 signals drive development through sequential steps during which alternative lineage potentials are lost and T-lineage specific gene expression (specification) occurs1–4. Notch is necessary for early T-cell development but its downstream effectors remain unclear5–7. We found that HMG box transcription factor, TCF-1, is highly upregulated in early thymic progenitors (ETPs)(Fig. 1a). Indeed, TCF-1 expression is upregulated when progenitors are exposed to Notch1 signals8. TCF-1 in normal T-lymphopoiesis TCF-1 deficiency greatly reduces thymic cellularity but does not abrogate T-cell development9–11(Fig. S1). When TCF-1−/ − progenitors were assessed in the absence of competition in irradiated mice, small numbers of T-lineage cells developed (Fig. S2a). Th