A role for beta-catenin in development and disease.

The WNTs are a family of proteins that function as short-range signaling factors and regulate many developmental processes. Mutational defects in WNT signaling also have a major contributing role in a broad spectrum of cancers. In the canonical WNT signaling pathway, extracellular WNT proteins stabilize levels of beta-catenin in the cytosol through a network of proteins. Stabilized beta-catenin enters the nucleus and binds to TCF/LEF family members. TCF/LEF family members are DNA-binding factors which recruit transcriptional repressors in the absence of beta-catenin. Interaction with beta-catenin results in transactivation of TCF/LEF target genes. Here, I describe the creation of an inducible beta-catenin construct and its use in a variety of settings. The construct was first shown to activate expression of an idealized TCF/LEF reporter construct. The construct was next utilized in a focus formation assay modeling the loss of contact inhibition characteristic of transformed cells. Reversible activation of this construct offered the possibility to address the question of whether continuous beta-catenin/TCF signaling is required for maintenance of a transformed phenotype. Interestingly, an equivalent number of foci were formed following one day or three weeks of continuous activation of the construct. The construct was next expressed in the skin and hair follicles of mice to mimic the effects of short- and long-term Wnt exposure in a well characterized developmental system. Continuous activation of the construct resulted in profound hyperplasia of outer root sheath cells lining the hair follicles and other changes consistent with the initiation of an aberrant growth phase of the hair cycle. Remarkably, brief activation of the inducible beta-catenin construct in resting hair follicles resulted in a completely normal growth phase. Lastly, the inducible beta-catenin construct was used to aid in the identification and characterization of beta-catenin/TCF target genes. One such gene, the rat homolog of murine Peg13, was studied in greater detail. These studies demonstrate the requirement for careful regulation of beta-catenin/TCF signaling activity. A future challenge will be to specifically target the WNT signaling pathway in cancer while preserving that which is required for normal growth and development.PhDBiological SciencesGeneticsHealth and Environmental SciencesOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125766/2/3208561.pd