ROLE OF FRIZZLED RECEPTORS AND EMBRYOGENESIS

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Vertebrate embryonic patterning is the process of generating the proper cellular diversity from a collection of pluripotent cells and involves a series of sequential cell-cell communication cascades. Several families of secreted proteins have been identified whose role in development is to act as signaling molecules in these important communication pathways. Prominent among these molecular messengers are members of the transforming growth factor beta (TGF-beta), hedgehog, noggin, and wnt gene families. To date, receptors have been isolated for the TGF-beta superfamily, with the identification of the putative receptors for these other three important signaling molecules yet to be determined. We have characterized members of the frizzled family of receptor-like molecules from zebrafish and Xenopus to test whether these genes function in the patterning of the vertebrate embryo, serving perhaps as a receptor for the wnt gene family of secreted factors. We will pursue this set of vertebrate fz gene family members with the specific goals of: I. Molecular characterization of three members of the fz gene family during embryogenesis. II. Determination of th role of fz genes in embryonic development through the use of overexpression studies. III.Investigation of the zygotic fz gene function in zebrafish embryos. IV. Determination of maternal fz gene function in Xenopus embryos. V. Identification of the signaling cascade(s) mediated by fz family members during embryonic development. We will manipulate specific fz genes in both zebrafish and Xenopus embryos by microinjection of synthetic transcripts to ectopically overexpress fz genes during embryogenesis. We will generate zebrafish strains carrying mutations in fz genes to identify pathways required for zygotic fz gene function. The generation of Xenopus embryos depleted of a maternally- expressed fz gene using antisense oligonucleotides will be used to address the maternal function of fz genes in embryogenesis. Using these tools, we will identify the signaling cascades mediated by this family of receptor- like molecules in an attempt to understand in a broader context the role this new gene family plays in development.