Roles of a Wnt activator, Ccd1, in neural development

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Wnt signaling plays important roles in axis formation, differentiation, growth, axon guidance, and synaptogenesis. Wnt signal is transduced via three pathways, beta-catenin pathway, PCP pathway, and Calcium pathway. Although many molecules involved in the Wnt pathways have been identified, many questions regarding the regulation of Wnt signaling remain unresolved. Recently we identified a novel protein Ccd1 (Coiled-coil-DIX1) as third DIX-domain-containing protein from zebrafish. We showed that Ccd1 activates Wnt/beta-catenin pathway both in vitro and in vivo, and that it regulates neural patterning in zebrafish embryos. We also found that many Ccd1 isoforms are generated via differential promoter usage and alternative splicing in mouse. Among them, a novel isoform, named Ccd1A, contains one calponin homology (CH) domain in the N-terminus in addition to the coiled-coil and DIX domains found in the original isoform (named Ccd1B). From zebrafish, we isolated second gene, Ccd2, which encode both A and B subtypes. When heterogouly expressed in cultured cell lines, Ccd1B protein is present as small vesicles throughout cells, Ccd2A protein is co-localized with actin fibers. In addition, the cytoplasmic localization of Dishevelled (Dvl) protein is altered by forced expression of Ccd1A and Ccd1B, suggesting that Ccd1 protein interacts with Dvl in the cell. Although we generated knockout mice, they did not show any obvious phenotypes. When we overexpressed Ccd2 in zebrafish embryos, they showed curly tail-down phenotype, suggesting that Ccd1 plays a role in midline signaling.