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Pre-TCR-Induced β-Catenin Facilitates Traversal through β-Selection¹

Mai Xu^*, Archna Sharma^*, David L. Wiest and Jyoti Misra Sen^2,*

^* Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and Fox Chase Cancer Center, Division of Basic Sciences, 333 Cottman Avenue, Philadelphia, PA 19111

Pre-TCR induced signals regulate development of the β TCR lineage cells at the β-selection checkpoint. We have previously shown that conditional deletion of β-catenin, a central mediator of Wnt-β-catenin-T cell factor signaling pathway, impairs traversal through the β-selection checkpoint. We now provide a molecular basis for the impairment. We demonstrate that pre-TCR signals specifically stabilize β-catenin in CD4^–CD8^– double negative thymocytes during β-selection. Pre-TCR induced Erk activity was required to stabilize β-catenin. Enforced expression of stabilized β-catenin was sufficient to mediate aspects of β-selection including sustained expression of early growth response (Egr) genes. Consistently, deletion of β-catenin reduced induction of Egr gene expression by the pre-TCR signal and blocked efficient β-selection. Thus, we demonstrate that pre-TCR induced β-catenin sustains expression of Egr genes that facilitate traversal through the β-selection checkpoint.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jyoti Misra Sen, National Institute on Aging-National Institutes of Health, 08C218, Biomedical Research Center, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224. E-mail address: Jyoti-Sen{at}nih.gov

³ Abbreviations used in this paper: DN, double negative; DP, double positive; TCF, T cell factor; Egr, early growth response; CAT-Tg, β-catenin transgene; ChIP, chromatin immunoprecipitation; hCD25, human CD25; LEF, lymphocyte enhancer binding factor.