The Wnt pathway has emerged as a critical regulator of early axis specification in vertebrates. This proposal aims to determine how the Wnt pathway becomes activated in the early embryo, and how this leads to the induction of the Spemann organizer. In Xenopus, the Wnt pathway is activated by a sperm-induced rotation of the embryonic cortex. This activation does not require Wnt ligands, and may therefore be regulated intracellularly. Following the earlier discovery that a key event in Wnt- signalling is inhibition of the kinase GSK-3, this laboratory has recently identified a novel, inhibitory GSK-3 binding protein, GBP, and demonstrated that it is required for dorsal axis induction. A major aim of this proposal is to determine precisely how GBP inhibits the activity of GSK-3, which functions as part of a multi-protein complex. Since GBP may be localized or activated locally in response to cortical rotation, investigations will determine where GBP is found in the embryo, whether it is regionally modified, and whether it binds other proteins in the early Xenopus embryo. Additional studies will ask whether the regulation of Wnt signalling by GBP is used throughout development, or whether GBP is solely a specialized maternal regulator of the Wnt pathway used only for dorsal axis specification. A second major area will investigate specifically how the activation of the Spemann organizer is regulated. Since the organizer forms in response to a Wnt pathway-mediated transcriptional depression, the molecular basis of this depression will be investigated. Furthermore, the factors that restrict the formation of the organizer to the equator of the embryo will be investigated since the principle role of the cortical rotation is to ensure that the Wnt pathway is activated at the equator. Since the Wnt pathway is implicated in normal vertebrate development and oncogenesis, these studies will be important in understanding the molecular basis of birth defects and cancer.
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