Activation of Canonical Wnt Signaling Meets with Podocytopathy

Abstract

WNT signaling regulates a variety of cell fate decisions and developmental processes in species ranging from flies and worms to humans.1 Altered function of the WNT/β-catenin pathway occurs in a diverse array of human diseases, highlighting a crucial role for canonical WNT signaling in the regulation of cellular homeostasis, organ function, and control of tissue patterning during vertebrate embryogenesis. WNTs encompass a family of 19 secreted glycoproteins, short-range signaling molecules activating canonical (β-catenin dependent) and noncanonical (β-catenin independent) intracellular signaling cascades through alternate binding to Frizzled and LDL receptor–related protein 5 and 6 transmembrane receptors.2 WNT signals control levels of cytosolic β-catenin by inhibiting glycogen synthase kinase 3β. Nuclear translocation of activated β-catenin results in interaction with a number of negatively charged ligands including the leukemia and the T cell factor transcription factors. In addition to its intracellular signaling function, β-catenin constitutes a central component of adherens junctions through its interaction with cadherins and other cell adhesion molecules.1,3 A role for canonical Wnt signaling in renal development, specifically branching morphogenesis of the ureteric bud, is well established.4–6 Several Wnt components are implicated, including Wnt 44 and Wnt 9b.7 Deletion of β-catenin in renal epithelial progenitors results in failed condensation of metanephric mesenchyme with reduced nephron formation, whereas constitutive activation induces ectopic leukemia and the T cell factor–dependent transcripts.8 In the …