Wnts are secreted ligands which activate receptor-mediated signaling pathways. Vertebrate Wnts and their signaling pathways have been implicated in playing key roles in axis specification, in patterning mesoderm and the nervous system, in providing polarity to limbs, and in organogenesis. When inappropriately activated, components of the Wnt pathways may be linked to various human cancers notably colorectal cancer and melanoma. The current proposal represents a competing continuation application, to maintain funding for our work on Wnt genes and their signaling pathways in Xenopus. As the previous specific aims have largely been answered, our present proposal introduces new specific aims to address recent questions arising from this prior support. Whereas many of the previous specific aims asked embryological questions, the current focus is on Wnt signal transduction.
Aim 1 uses yeast-two hybrid screens, and mass spectroscopy analysis, to identify new components of the Wnt-1/Frizzled-1 pathway.
Aim 2 investigates the biochemistry of the distinct Wnt-5a/Frizzled-2 pathway which we discovered in the prior two project periods.
Aim 3 investigates the target genes of Wnt signaling and their functions in development. Given the high degree of conservation of the Wnt-1 signaling pathway in evolution, it is likely the results of this work in Xenopus will continue to directly apply to Wnt signaling in other vertebrates.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027525-09
Application #
6182132
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Klein, Steven
Project Start
1991-02-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
9
Fiscal Year
2000
Total Cost
$173,507
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Sheldahl, Laird C; Slusarski, Diane C; Pandur, Petra et al. (2003) Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. J Cell Biol 161:769-77
Cheyette, Benjamin N R; Waxman, Joshua S; Miller, Jeffrey R et al. (2002) Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell 2:449-61
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Larabell, C A; Torres, M; Rowning, B A et al. (1997) Establishment of the dorso-ventral axis in Xenopus embryos is presaged by early asymmetries in beta-catenin that are modulated by the Wnt signaling pathway. J Cell Biol 136:1123-36
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Ekker, S C; McGrew, L L; Lai, C J et al. (1995) Distinct expression and shared activities of members of the hedgehog gene family of Xenopus laevis. Development 121:2337-47

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