Wnt signaling is a major player during development and its misregulation often leads to disease, especially cancer. The negative feedback Wnt regulator homologs, Nkd1 and Nkd2, have been shown to inhibit Wnt signaling during development, and current evidence suggests that Nkds degrade Dvl proteins to antagonize Wnt signaling. Here, we demonstrate that during early zebrafish development Nkd1 does not alter either endogenous or exogenous levels of Dvl2. Furthermore, Dvl2 does not affect the levels of Nkd1. Cumulatively, these results demonstrate that Dvl2 is a ubiquitous and stable protein and that Nkds may not always function to degrade Dvl proteins as a method of inhibiting Wnt signaling.
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.
Colorectal cancer (CRC), the most common form of gastrointestinal (GI) tract cancer, is globally the third leading cause of cancer and is associated with significant mortality (1). Approximately 90% of CRC cases are sporadic, caused by somatic mutations leading to the progression of invasive carcinomas (2). There are numerous risk factors associated with the development of CRC, and the disease is more common in industrialized countries than it is in the developing world (1). Poor diet (in particular, a diet that is low in fiber and high in fat) appears to be a major influencing factor for disease development and progression, and recently it has been recognized that gut microbes may act as the interface between dietary factors and tumor development (reviewed in reference 3). This chapter will review the pathways that lead to CRC, what is currently known about microbial involvement in these processes, and how these may be manipulated therapeutically.
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