A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities

Wnt ligands are secreted morphogens that control multiple developmental processes during embrygenesis and adult homeostasis. A diverse set of receptors and signals have been linked to individual Wnts, but the lack of tools for comparative analysis has limited the ability to determine which of these signals are general for the entire Wnt family, and which define subsets of differently acting ligands. We have created a versatile Gateway library of clones for all 19 human Wnts. An analysis comparing epitope-tagged and untagged versions of each ligand shows that despite their similar expression at the mRNA level, Wnts exhibit considerable variation in stability, processing and secretion. At least 14 out of the 19 Wnts activate beta-catenin-dependent signaling, an activity that is cell type-dependent and tracks with the stabilization of beta-catenin and LRP6 phosphorylation. We find that the core Wnt modification and secretion proteins Porcupine (PORCN) and Wntless (WLS) are essential for all Wnts to signal through beta-catenin-dependent and independent pathways. This comprehensive toolkit provides critical tools and new insights into human Wnt gene expression and function. (C) 2012 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.