The role of glycogen synthase kinase 3 in early xenopus development

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The role of glycogen synthase kinase 3 in early xenopus development

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Title: The role of glycogen synthase kinase 3 in early xenopus development
Author: Pierce, Sarah B
Abstract: Experiments early in this century indicated that dorsoventral axis formation in the Xenopus embryo requires the activity of the Spemann organizer, or gastrula organizer. Cell and cytoplasmic transplantation studies subsequently defined the earlier acting blastula organizer, or Nieuwkoop center, which induces formation of the Spemann organizer. Several secreted factors, including members of the Wnt family, were found to mimic the Nieuwkoop center when ectopically expressed, but none of these were shown to be endogenously required for dorsoventral axis formation.Here I describe the isolation and characterization of Xenopus glycogen synthase kinase 3 (Xgsk-3), a serine/threonine kinase which is homologous to a component of the intracellular signaling pathway utilized by the Drosophila Wnt homolog Wg. Using a dominant-negative mutant of Xgsk-3, I show that Xgsk-3 is a negative regulator of the dorsal fate. This indicates that Wnt and Wg signal through homologous pathways and that the Wnt pathway is necessary for endogenous axis formation. In addition, dominant-negative Xgsk-3 acts non-cell-autonomously, indicating that a subsequent intercellular signal is required for Spemann organizer induction.The isolation and characterization of, GBP, a protein that binds Xgsk-3, is also described. GBP induces the formation of a secondary axis, suggesting that GBP interferes with the action of Xgsk-3, but it does not inhibit the enzymatic activity of Xgsk-3. However, GBP joins a complex with Xgsk-3, APC and $\beta$-catenin. Xgsk-3 regulates dorsoventral axis formation by negatively regulating the stability of $\beta$-catenin and APC is thought to participate in this process. I present a model in which GBP induces axis formation by disrupting the function of this complex.It was found that overexpression of Xgsk-3 in the prospective ectoderm resulted in an expansion of the cement gland and other non-neural ectodermal tissues at the expense of lateral ectoderm, without disrupting the borders of the neural plate. This resulted from a greater responsiveness of the ectoderm to cement gland-inducing signals, which could be mimicked by the secreted factor noggin. A model for the role of Xgsk-3 in ectodermal patterning is presented which considers the expression of Wnt family members that could regulate Xgsk-3 during the time of cement gland induction and the endogenous role of noggin as an inhibitor of BMP-4 signaling.
Description: Thesis (Ph. D.)--University of Washington, 1997
URI: http://hdl.handle.net/1773/9204

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