Somatic activation of β-catenin bypasses pre-TCR signaling and TCR selection in thymocyte development

Abstract

Mutation or ablation of T cell factor 1 and lymphocyte enhancer factor 1 indicated involvement of the Wnt pathway in thymocyte development. The central effector of the Wnt pathway is β-catenin, which undergoes stabilization upon binding of Wnt ligands to frizzled receptors. We report here that conditional stabilization of β-catenin in immature thymocytes resulted in the generation of single positive T cells that lacked the αβ TCR and developed in the absence of pre-TCR signaling and TCR selection. Although active β-catenin induced differentiation in the absence of TCRs, its action was associated with reduced proliferation and survival when compared to developmental changes induced by the pre-TCR or the αβ TCR.

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Figure 1: Activation of β-catenin in the thymi of β-catThyΔex3 mice.
Figure 2: Activation of β-catenin in immature thymocytes altered thymocyte development.
Figure 3: T cell development proceeded independently of TCRβ-selection.
Figure 4: Activation of β-catenin rescued RAG-2−/−–induced developmental arrest.
Figure 5: Activation of β-catenin altered cell cycling and total thymocyte numbers.
Figure 6: Thymocytes expressing activated β-catenin show an apoptotic phenotype.

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Acknowledgements

We thank C. Wilson, C. Beard and S. Korsmeyer for the lck-cre mice; A. Siermann and the DFCI sorting facility for technical assistance; P. Sicinski, L. Haughn and C. Borowski for discussions and critical reading of the manuscript; and L. Holcomb for help in preparing the manuscript. F. G. and K. K. also thank Artemis for support. Supported by grants from the Ministry of Education, Science, Sports and Culture; Organization for Pharmaceutical Safety and Research, Japan; the Joint Research Fund between the University of Tokyo and Banyu Pharmaceutical Co; and NIH grants R01A145846 and R01AI47281.

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Correspondence to Harald von Boehmer.

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