Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules.
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 beta-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., beta-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.
Weerkamp
Floor
F
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Baert
Miranda R M
MR
Naber
Brigitta A E
BA
Koster
Esther E L
EE
de Haas
Edwin F E
EF
Atkuri
Kondala R
KR
van Dongen
Jacques J M
JJ
Herzenberg
Leonard A
LA
Staal
Frank J T
FJ
D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin