Phylogenetic and regulatory region analysis of Wnt5 genes reveals conservation of a regulatory module with putative implication in pancreas development

BACKGROUND: Wnt5 genes belong to the large Wnt family, encoding proteins implicated into several tumorigenic and developmental processes. Phylogenetic analyses showed that Wnt5 gene has been duplicated at the divergence time of gnathostomata from agnatha. Interestingly, experimental data for some species indicated that only one of the two Wnt5 paralogs participates in the development of the endocrine pancreas. The purpose of this paper is to reexamine the phylogenetic history of the Wnt5 developmental regulators and investigate the functional shift between paralogs through comparative genomics. RESULTS: In this study, the phylogeny of Wnt5 genes was investigated in species belonging to protostomia and deuterostomia. Furthermore, an in silico regulatory region analysis of Wnt5 paralogs was conducted, limited to those species with insulin producing cells and pancreas, covering the evolutionary distance from agnatha to gnathostomata. Our results confirmed the Wnt5 gene duplication and additionally revealed that this duplication event included also the upstream region. Moreover, within this latter region, a conserved module was detected to which a complex of transcription factors, known to be implicated in embryonic pancreas formation, bind. CONCLUSIONS: Results and observations presented in this study, allow us to conclude that during evolution, the Wnt5 gene has been duplicated in early vertebrates, and that some paralogs conserved a module within their regulatory region, functionally related to embryonic development of pancreas. Interestingly, our results allowed advancing a possible explanation on why the Wnt5 orthologs do not share the same function during pancreas development. As a final remark, we suggest that an in silico comparative analysis of regulatory regions, especially when associated to published experimental data, represents a powerful approach for explaining shift of roles among paralogs. REVIEWERS: This article was reviewed by Sarath Janga (nominated by Sarah Teichmann), Ran Kafri (nominated by Yitzhak Pilpel), and Andrey Mironov (nominated by Mikhail Gelfand).