Seminar

Novel regulators and effectors of canonical and non-canonical Wnt signaling

Andreas Jenny, PhD

The Wnt-Frizzled(Fz)/beta-Catenin and Fz/planar cell polarity (PCP) pathways are related signaling pathways crucial for the induction and regulation of many developmental processes in vertebrates and invertebrates. Aberrant Wnt signaling leads to a variety of diseases such as cancer and birth defects. We have identified dWnk (Drosophila With No Lysine[K] kinase] as a previously unknown modulator of canonical Wnt signaling. Wnk family kinases are known for their function in regulation of blood pressure and cell volume in vertebrates. Our data indicate that dWnk affects peak levels of canonical Wnt signaling, as loss of dwnk in mutant clones leads to loss of wing margin structures concomitant with a loss of a high-threshold, direct Wnt target. We have thus identified a developmental function for the fly ortholog of kinases that cause Grodon syndrome in humans, characterized by hyperkalemia, acidosis and high blood pressure. Planar cell polarity (PCP) signaling regulates the establishment of polarity within the plane of an epithelium and is governed by the non-canonical Fz/Planar Cell Polarity pathway, in which a Wnt signals through a Frizzled receptor leading to nuclear responses, as well as to cytoskeletal changes mediated by Rho Kinase. In an attempt to identify novel components of non-canonical Wnt/Fz-PCP signaling, we conducted a genome-wide molecular screen to identify novel Rho kinase substrates potentially mediating changes of the cytoskeleton. One of the substrates we identified the formin Frl. Formins are known to regulate actin polymerization dynamics and the Xenopus formin XDAAM was previously shown to be activated by Dishevelled during convergent extension, a process controlled by PCP signaling. Indeed, preliminary data show that knock-down of Frl causes PCP phenotypes.