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A critical role for TCF-1 in T-lineage specification and differentiation

Abstract

The vertebrate thymus provides an inductive environment for T-cell development. Within the mouse thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential haematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that a transcription factor, T-cell factor 1 (TCF-1; also known as transcription factor 7, T-cell specific, TCF7), 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 bone marrow (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 and 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.

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Figure 1: TCF-1 is necessary for early T-lineage development and specification.
Figure 2: Ectopic expression of TCF-1 elicits T-lineage cells in vitro.
Figure 3: TCF-1 upregulates expression of T-lineage specific genes.
Figure 4: TCF-1 is expressed in the earliest T cell progenitors and is downstream of Notch1.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the Gene Expression Omnibus database under accession numbers GSE26559 and GSE26560.

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Acknowledgements

We thank H. Clevers for permission to use TCF-1−/− mice and W. Pear, S. Reiner, C. Bassing, R. Sen and W. Bailis for critical comments. This work was supported by NIH grant AI059621 and a Scholar Award from the Leukemia and Lymphoma Society (A.B.), and institutional training grants T32AI055428 (B.N.W.) and T32CA09140 (A.W.-S.C.).

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B.N.W., A.W.-S.C. and A.B. designed and performed the experiments. Q.Y., Y.Y.-O. and A.C. helped with experiments. O.S. provided mice and technical assistance. B.N.W. and A.B. wrote the paper.

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Correspondence to Avinash Bhandoola.

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The authors declare no competing financial interests.

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Weber, B., Chi, AS., Chavez, A. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011). https://doi.org/10.1038/nature10279

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