title: Nkd1 functions as a passive antagonist of Wnt signaling.
abstract: Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1's ability to antagonize canonical Wnt/β-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/β-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Angonin
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Van Raay
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C525385:Nkd1 protein, zebrafish; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C491759:vangl2 protein, zebrafish; C094521:wnt8a protein, zebrafish