ABSTRACT
The Wnt and Frizzled (Fz) gene families of signaling molecules were first discovered and characterized in Drosophila. Studies in the past several years have revealed the involvement of Wnt signaling in a number of different mammalian systems, influencing the developmental potential of a diverse pool of cells in these organisms.1,2 Specifically, Wnt signaling has been shown to be a key regulator in stem cell renewal and differentiation.3,4 For example, targeted disruption of Wnt signaling by loss of function mutation(s) or overexpression of components of the pathway are linked to dramatic phenotypes, as we have recently shown in mesenchymal stem cells (MSCs).5,6
Over 19 members of the Wnt family have been identified in mammals and, depending on the specific Wnt, signaling may proceed via canonical and/or non-canonical Wnt pathways7,8
(Figure 25.1). Canonical Wnt signaling involves the binding of a Wnt ligand to a Fz receptor, and to the Wnt co-receptor, low-density lipoproteinrelated protein 5 (LRP5) (Figure 25.1A). The binding of these components activates the cytoplasmic protein Disheveled (Dvl), leading to an inhibition of phosphorylation of β-catenin by glycogen synthase kinase-3β (GSK-β). β-Catenin
is stabilized and subsequently translocates to the nucleus, where it binds with members of the T-cell factor (TCF) and lymphoid enhancer factor (LEF) transcription factor families, resulting in the enhanced expression of target genes, such as c-myc and cyclin D1.9 In the absence of a Wnt ligand, β-catenin is phosphorylated by GSK-3β, in association with axin and adenomatous polyposis coli (APC), thus targeting β-catenin for ubiquitinylation and subsequent degradation by proteasomes.1
