The beta-catenin pathway is involved in normal B cell development and function (83.3)

Abstract

Abstract Wnt/Fzd signaling plays a key role in development, stem cell maintenance, and tumorigenesis, particularly via stabilization of ß-catenin protein levels. TCF-1 and LEF-1 knockout mice suggested a role for this pathway in lymphoid development as well. We have previously shown that Fzd9−/− mice exhibit a decrease in pre-B cells at a stage when self-renewing division is occurring in preference over further differentiation, prior to light chain Ig recombination (Hardy C-D). We now report further evidence for a role of ß-catenin in normal B cell function and development. By flow cytometric analysis, we find that cellular ß-catenin levels rise at precisely the stage of B cell development that shows diminished numbers in Fzd9−/− mice. Expression of LEF-1, the transcriptional partner of ß-catenin, also is tightly regulated during this developmental sequence by differential transcription of full length and dominant negative forms, further suggesting that Wnt/Fzd signals impact on B-cell lymphopoiesis. In mature B-cells, activation through BCR, Toll-like receptors, and CD40 all induce an increase in beta-catenin protein levels, while changes in the expression of genes involved in both positive and negative regulation of canonical Wnt signaling are differentially regulated by these stimuli, highlighting a potential novel role for this pathway in B-lymphocyte proliferation, differentiation, and survival.