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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112369-03
Application #
7229547
Study Section
Special Emphasis Panel (ZRG1-DEV-1 (01))
Program Officer
Yassin, Rihab R,
Project Start
2005-07-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$220,974
Indirect Cost
Name
University of Iowa
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Schneider, Patricia N; Slusarski, Diane C; Houston, Douglas W (2012) Differential role of Axin RGS domain function in Wnt signaling during anteroposterior patterning and maternal axis formation. PLoS One 7:e44096
Baye, Lisa M; Patrinostro, Xiaobai; Swaminathan, Svetha et al. (2011) The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. Hum Mol Genet 20:1467-77
Westlake, Christopher J; Baye, Lisa M; Nachury, Maxence V et al. (2011) Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proc Natl Acad Sci U S A 108:2759-64
Tao, Hirotaka; Manak, J Robert; Sowers, Levi et al. (2011) Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am J Hum Genet 88:138-49
Sundberg, Thomas B; Darricarrere, Nicole; Cirone, Pasquale et al. (2011) Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37. Chem Biol 18:1300-11
Sang, Liyun; Miller, Julie J; Corbit, Kevin C et al. (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513-28
Wright, Kevin J; Baye, Lisa M; Olivier-Mason, Anique et al. (2011) An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev 25:2347-60
Pretorius, Pamela R; Aldahmesh, Mohammed A; Alkuraya, Fowzan S et al. (2011) Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. Hum Mol Genet 20:1625-32
Pretorius, Pamela R; Baye, Lisa M; Nishimura, Darryl Y et al. (2010) Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS Genet 6:e1000884
Freisinger, Christina M; Fisher, Rory A; Slusarski, Diane C (2010) Regulator of g protein signaling 3 modulates wnt5b calcium dynamics and somite patterning. PLoS Genet 6:e1001020

Showing the most recent 10 out of 22 publications