Wnt Signaling in the Thymus Is Regulated by Differential Expression of Intracellular Signaling Molecules

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 9; pp. 3322 - 3326
• Main Authors: Weerkamp, Floor, Baert, Miranda R. M., Naber, Brigitta A. E., Koster, Esther E. L., de Haas, Edwin F. E., Atkuri, Kondala R., van Dongen, Jacques J. M., Herzenberg, Leonard A., Staal, Frank J. T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28-02-2006; National Acad Sciences
• Subjects: beta Catenin - metabolism; Biological Sciences; Biology; Cell Differentiation; Cells; Developmental biology; Gene Expression Regulation; Humans; Immune system; Immunology; Internet service providers; Liver cells; Mice; Molecules; Receptors; Signal Transduction; Stem cells; T lymphocytes; Thymocytes; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; Time Factors; Wnt Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0511299103

Wnt signaling is essential for T cell development in the thymus, but the stages in which it occurs and the molecular mechanisms underlying Wnt responsiveness have remained elusive. Here we examined Wnt signaling activity in both human and murine thymocyte populations by determining β-catenin levels, Tcf-reporter activation and expression of Wnt-target genes. We demonstrate that Wnt signaling occurs in all thymocyte subsets, including the more mature populations, but most prominently in the double negative (DN) subsets. This differential sensitivity to Wnt signaling was not caused by differences in the presence of Wnts or Wnt receptors, as these appeared to be expressed at comparable levels in all thymocyte subsets. Rather, it can be explained by high expression of activating signaling molecules in DN cells, e.g., p3-catenin, plakoglobin, and long forms of Tcf-1, and by low levels of inhibitory molecules. By blocking Wnt signaling from the earliest stage onwards using overexpression of Dickkopf, we show that inhibition of the canonical Wnt pathway blocks development at the most immature DN1 stage. Thus, responsiveness to developmental signals can be regulated by differential expression of intracellular mediators rather than by abundance of receptors or ligands.