Rapid advances in the characterization of eukaryotic genomes have led to an awareness of the increasing complexity in cellular growth, patterning and polarization controls and the mechanisms by which their regulation (and deregulation) contributes to normal development and/or disease. Signaling pathways are interconnected through multiple effectors that determine cell fate, growth, and/or polarization. The Wnt-signaling pathways constitute one such critical evolutionarily conserved key regulator pathway network. Loss of or (ectopic) constitutive Wnt-signaling is found associated with many congenital diseases and/or cancer. Wnt growth factors can signal through several effector pathways sharing the Wnt receptor family, the Frizzled (Fz) receptors, and their first known cytoplasmic effector proteins, Dishevelled (Dsh or Dvl in mammals). The two main Wnt-pathways are generally referred to as Wnt-Fz/b-cat (or canonical Wnt) signaling and the Wnt-Fz/PCP (planar cell polarity) pathway. They diverge downstream of Dsh. These distinct Wnt-Fz pathways importantly regulate different cellular responses, ranging from growth control to cellular polarization, and thus the precise regulation of pathway specificity is critical throughout development and cellular homeostasis.
The program goals are to elucidate mechanisms of Wnt-Frizzled signaling regulation and signaling specificity based on novel perspectives of discoveries made within the laboratories of the PIs. The overall long-term objectives of this research are to develop understanding of mechanisms (and associated molecular and diagnostic tools) by which Wnt-Frizzled signaling regulates the different aspects of its signaling outcome in cellular differentiation and function. This program brings together a senior group of investigators from different disciplines and with complementary expertise in mammalian cell biology, vertebrate development, and Drosophila patterning focused on important and novel aspects of Wnt-Fz signaling biology and regulation as identified within the program. The overall significance of this research effort is that major insights gained in the investigation of cellular Wnt-signaling regulation offer the potential for improved therapeutic approaches to specific diseases. In addition, an understanding of Wnt-Fz signaling regulation in mediating normal cell (and stem cell) behavior could aid in the design of therapeutic interventions, which do not disrupt critical processes important to tissue homeostasis. The synergy of the Program is possibly best illustrated by the efforts to identify specific small molecules affecting Wnt signaling strength or signaling outcome, and the coordinated approach of each project with the other projects of the application and the Small Molecule Discovery Core. This Chemical Genetics approach is at the forefront of the technology through joint efforts of the project leaders and the Core Director. This coordination has already established its ability to accelerate the pace of discovery. Overall, the combination of complementary assays and distinct species should be of immediate relevance for potential therapeutic application of any of the small molecules identified in this program.