Beta-catenin activity has a profound impact in both development and cancer. Activation of the canonical Wnt path (Wnt/Beta-catenin) results in the accumulation of Beta-catenin. Non-canonical Wnts influence cell movement and modulate calcium release (Wnt/Ca2+). We have demonstrated that genetic depletion of Wnt-5 (pipetail, ppt), a non-canonical Wnt, results in reduced Ca2+ release and increased beta-catenin accumulation in zebrafish. How the different Wnt pathways interact is not well known. We hypothesize that non-canonical Wnts, through Ca2+ modulation, function as negative-regulators of Wnt/Beta-catenin signaling, raising the fascinating possibility that Wnt-5 is a potential tumor suppressor. Our goal is to use molecular-genetic analyses coupled with in vivo imaging to investigate the mechanisms of Wnt/Ca2+ activity in development and in tumor suppression.
In Specific Aim 1, we determine if Beta-catenin stabilization in Wnt-5 mutant (ppt) embryos is a direct result of Wnt/Ca2+ function. We will determine whether the facilitated beta-catenin activity in ppt mutants can be suppressed by Wnt-5 misexpression, or by manipulating Ca2+ release.
In Specific Aims 2 and 3, we explore several potential mechanisms by which Wnt/Ca2+ activity could be antagonizing Wnt/Beta-catenin activity. We will determine if Wnt-5-mediated phenotypes (gain- and loss-of-function) require the activity of Axin and/or GSK, both key players in canonical Wnt signaling. The antagonistic interactions could be mediated by competition for Dsh (Dishevelled), a protein that signals in both Wnt pathways. We will investigate the role of naked cuticle, a calcium sensor that binds Dsh, as a potential mediator of Dsh sequestration to a particular signaling pathway. And lastly, we have found that Wnt/Ca2+ mutants develop spontaneous tumors.
In aim 4, we will characterize the affected tissues and investigate the biological role of Wnt/Ca2+ activity as a potential tumor suppressor. In this new initiative in the lab, we apply our developmental biology expertise with in vivo image analysis of the whole organism to generate new insights into the mechanisms of tumor formation and growth
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