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.

NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling

“…Interestingly, YAP1 restricts Wnt signaling independently of the β-catenin destruction complex by suppressing nuclear translocation of Dvl. Thus, we propose that in concordance with the "passive antagonist" model [32], Nkd1 might directly influence the nuclear Dvl function in cells displaying hyperactive Wnt signaling.…”

“…Simultaneous inactivation of both vertebrate paralogs Nkd1 and Nkd2 in the mouse leads to only subtle alterations in the morphology of cranial bones and slightly reduced litter size, but the mice are otherwise normal [31]. Based on these and other results mainly obtained in zebrafish [30], Angonin and Van Raay proposed that Nkd1 functions as a "passive antagonist" that acts only when the Wnt signaling levels exceed some threshold [32].…”

Functional architecture of deleterious genetic variants in the Wrangel Island mammoth genome

“…The HYLS1 S186L mutant did, however, appropriately localize to centrioles and did not have any dominant negative effects in the absence of depletion of the endogenous protein ( Defects in sperm morphology are among the most common consequences of reduced genetic diversity and inbreeding (Asa et al, 2007;Shorter et al, 2017) Island mammoth associated with sperm defects and male infertility is Naked cuticle 1 (NKD1), which encodes a passive antagonist of the Wnt/TCF-LEF signaling pathway (Angonin and Van Raay, 2013;Van Raay et al, 2007;. The Wrangel Island mammoth A88V substitution occurred at a site that is nearly invariant for alanine or serine in diverse vertebrates ( Fig.…”

Feedback control of Wnt signaling based on histidine cluster co-aggregation between Naked/NKD and Axin

“…Furthermore, overexpression of NKD paralogs can antagonize both canonical and non-canonical Wnt signal transduction in fish and frog embryos (Hu et al, 2010;Marsden et al, 2018;Van Raay et al, 2007;Yan et al, 2001), while depletion of Nkd1 and Nkd2 in early zebrafish embryos results in hyperactivation of canonical Wnt target genes. In addition, Nkd1 depletion produces non-canonical defects in left-right asymmetry signaling (Marsden et al, 2018;Schneider et al, 2010), exacerbates convergent extension defects under certain conditions (Van Raay et al, 2007) and sensitizes embryos to hyperactive Wnt signaling (Agonin and Van Raay, 2013). Curiously, in the light of these defects caused by Naked/NKD loss in fly and fish embryos, Nkd does not appear to be essential in mice: five doubleknockout mice were bread from heterozygous parents, although these were born at sub-Mendelian ratios, and with subtle bone abnormalities reminiscent of Axin2-deficient mice .…”