WNT3 AND AXIS FORMATION AND CNS DEVELOPMENT

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Within the last decade, members of the Wnt gene family have been shown to possess axis-inducing activity in vertebrate embryos. Unfortunately, there is no expression or genetic data that would suggest that these genes play this role in normal development. Very recently, however, it was found that a Wnt gene, Wnt-3, is expressed prior to gastrulation and that mice homozygous for a mutation at this locus lack a body axis. Notwithstanding these long awaited results, there are many questions that remain unanswered. Therefore the following experiments are proposed: Specific aim number 1. Determine the basis for the body axis defects in Wnt-3 mutant mouse embryos. 1.1 Wnt-3 expression will be examined at the histological level in E5.5-E7.5 embryos. 1.2 Chimeric embryos derived from wildtype and Wnt-3 mutant cells will be generated to determine which Wnt-3 expressing regions from early embryos are essential for body axis formation. 1.3 The axis inducing activity of Wnt-3 will be tested by injected Wnt-3 mRNA into Xenopus embryos. Specific aim number 2. Determine the relationship between Wnt-3 and Axin ( a repressor or axis formation and of the Wnt signaling pathway) in the process of axis formation. 2.1 Wnt-3/Axin double mutant mice will be generated to determine whether the supernumerary axes present in Axin-/- mice is dependent of Wnt-3 signaling. Specific aim number 3. Determine later functions of Wnt-3 during embryogenesis. 3.1 Using a conditional allele of Wnt-3 (Wnt-3c) the gene product will be eliminated in the primitive streak to determine whether Wnt-3 is required for the maintenance of primitive streak formation. 3.2 Using the Wnt-3c allele, Wnt-3 will be eliminated specifically from the neural tube to determine its role in patterning the central nervous system.