The vertebrate body plan forms as a result of a cascade of inductive interactions. Embryonic cells are instructed to proliferate or to differentiate depending on the signals they receive from their neighbors. Different growth factors may perform this signaling role during normal development, but can cause cancer if provided in the inappropriate time or to the inappropriate recipient cell. The establishment of dorsoventral polarity, which is an essential component of body plan determination, occurs prior to the onset of zygotic transcription and may be mediated by Wnt protein(s). Wnts are a family of highly conserved signaling proteins related to the Wnt1 protooncogene, which seem to play important developmental roles. However, little is known about the reception and transduction of Wnt signals. Genetic studies in Drosophila have identified the dishevelled gene product which functions cell autonomously and is required for Wnt signaling. Our preliminary experiments have shown the existence of maternally expressed Xenopus homologue of dsh (Xdsh). We are going to use biochemical and embryological approaches in the Xenopus system to investigate how Xdsh functions during vertebrate development. We propose, first, to study spatial and temporal expression pattern of Xdsh using in situ hybridization and immunocytochemistry. To investigate the developmental role of Xdsh, we will inactivate the protein function in embryos microinjected with antisense oligonucleotides or locally overexpress the protein by Xdsh mRNA injection. Experiments will be conducted to determine whether Xdsh is necessary for the cell response to embryonic inducers during dorso-ventral axis determination and during nervous system development. Antibodies to Xdsh and cDNA expression cloning will be used to identify proteins physically interacting with Xdsh in embryonic cells. These experiments should lead to better understanding of both general mechanisms of vertebrate pattern formation and of the molecular basis of Wnt signal transduction.
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