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Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function¹

Saulius Zuklys^*, Jason Gill^*, Marcel P. Keller^*, Mathias Hauri-Hohl^*, Saule Zhanybekova^*, Gina Balciunaite^*, Kyung-Jae Na^*, Lukas T. Jeker^*, Katrin Hafen^*, Noriyuki Tsukamoto, Takashi Amagai, Makoto M. Taketo, Werner Krenger^* and Georg A. Holländer^2,*

^* Department of Clinical-Biological Sciences, Laboratory of Pediatric Immunology, University of Basel, and Basel University Children’s Hospital; Basel, Switzerland; Department of Immunology and Microbiology, Meiji University of Oriental Medicine, and Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation of the canonical Wnt signaling pathway by a stabilizing mutation of β-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function.

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 work was supported by the Swiss National Science Foundation Grants 3100-61782.00 (to W.K.) and 3100-68310.02 (to G.A.H.), by a grant from the European Community 6^th Framework Program Euro-Thymaide Integrated Project (to G.A.H.), by Grant ROI-A1057477-01 from the National Institutes of Health (to G.A.H.), and the Basel Cancer League (to W.K. and M.P.K.). J.G. is a CJ Martin Fellowship recipient from the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Georg A. Holländer, Laboratory of Pediatric Immunology, Department of Clinical-Biological Sciences, Center for Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. E-mail address: georg-a.hollaender{at}unibas.ch

³ Abbreviations used in this paper: DN, double negative; TEC, thymic epithelial cell; CK, cytokeratin; Wif, Wnt inhibitory factor; Dkk, Dickkopf; PAC, P1 artificial chromosome; wt, wild type.