Wnt Secretion from Epithelial Cells and Subepithelial Myofibroblasts Is Not Required in the Mouse Intestinal Stem Cell Niche In Vivo

Wnt signaling is a crucial aspect of the intestinal stem cell niche required for crypt cell proliferation and differentiation. Paneth cells or subepithelial myofibroblasts are leading candidate sources of the required Wnt ligands, but this has not been tested in vivo. To abolish Wnt-ligand secretion, we used Porcupine (Porcn) conditional-null mice crossed to strains expressing inducible Cre recombinase in the epithelium, including Paneth cells (Villin-CreERT2); in smooth muscle, including subepithelial myofibroblasts (Myh11-CreERT2); and simultaneously in both compartments. Elimination of Wnt secretion from any of these compartments did not disrupt tissue morphology, cell proliferation, differentiation, or Wnt pathway activity. Thus, Wnt-ligand secretion from these cell populations is dispensable for intestinal homeostasis, revealing that a minor cell type or significant and unexpected redundancy is responsible for physiologic Wnt signaling in vivo. [Display omitted] •Porcn knockout in candidate intestinal niche cells eliminates Wnt secretion in vivo•Wnts from Paneth cells or intestinal subepithelial myofibroblasts are dispensable•Physiologic intestinal Wnt signaling is more complex than current views suggest Wnt signaling is crucial in the intestinal stem cell niche, but the cell types producing essential Wnt ligands are unknown. Using Porcn conditional-null mice, Shivdasani and colleagues eliminated Wnt ligand secretion from intestinal epithelium, including Paneth cells; smooth muscle, including subepithelial myofibroblasts; and in both compartments. They found no defects in intestinal homeostasis or Wnt signaling, revealing unanticipated niche redundancy or complexity.