Emeritus Laboratory Rolf Kemler
The dual role of ß-catenin in cadherin-mediated adhesion and as the downstream effector of the canonical Wnt signaling pathway is addressed by combining in-vitro and in-vivo analysis. We conditionally deleted ß-catenin from the entire posterior region of the embryo after gastrulation. In addition, we are dissecting the adhesive and signaling functions of ß-catenin prior to and throughout gastrulation by conditionally replacing the wild type protein with mutant isoforms impaired in specific molecular interactions and functions. We have isolated several ES cell lines with pre-determined genotypes for E-cadherin and ß-catenin.
We found that ß-catenin is required to maintain genomic stability in mouse ES cells. Additionally we report a molecular link between Wnt/ß-catenin signaling and the expression of the telomerase subunit Tert. ß-catenin–deficient mouse embryonic stem (ES) cells have short telomeres; conversely, ES cells expressing an activated form of ß-catenin (ß-cat-delEx3/+) have long telomeres. We show that ß-catenin regulates Tert expression through the interaction with Klf4, a core component of the pluripotency transcriptional network. ß-catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. We uncover a previously unknown link between the stem cell and oncogenic potential whereby ß-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer.