Biological Roles of Galectins

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Galectins are a family of soluble 2-galactoside-binding proteins. Several galectin types have been described (proto, chimera, and tandem-repeat), each endowed with a unique molecular structure, biochemical properties, and taxonomic distribution. Embryonic expression patterns and affinity for extracellular matrix glycoproteins have led to propose that galectins mediate developmental processes, whereas their expression in macrophages, eosinophils and basophils suggests, and their recently established recognition properties for microbes, suggest their functions in immunity. Because of its external fertilization and development, transparent embryos, short generation time, powerful genetic systems, and extensive genomic resources, the zebrafish (Danio rerio) is a useful model for in vivo studies of development and immunology. We have made substantial contributions to the biochemical, structural, and evolutionary characterization of galectins in zebrafish: we identified proto, chimera, tandem-repeat, and chimeric tandem-repeat galectins, and characterized their developmental expression and tissue distribution. We performed preliminary functional analyses: knockdown embryos for proto type galectins exhibit disrupted muscle fiber organization, retinal regeneration, and an underdeveloped heart, while chimera, tandem-repeat, and chimeric tandem-repeat galectins are up-regulated upon immune challenge. We hypothesize that (I) the proto galectins Drgal1-L2 and Drgal1-L4 play a critical role in notochord development, and are indirectly involved in myoblast differentiation and heart development through signals from the notochord or neural tube. Further, (II) the proto galectin DrGRIFIN plays an important role in eye lens development. Finally, (III) the chimeric and tandem-repeat galectins (Drgal3-L1, Drgal9-L3, and Drgal9-L4) are directly involved in innate immune responses by interacting with potential pathogens and/or by recruiting phagocytic cells to sites of acute inflammation, and/or indirectly, by interacting with receptors on their surface, inducing their activation upon infectious challenge. The proposed studies will yield (a) novel information on the biological role(s) of galectins in development and immunity in the zebrafish model; (b) novel information concerning the molecular mechanisms of cell-cell, cell-ECM, and cell-pathogen interactions that modulate embryonic development and immune functions shared between teleost fish and higher vertebrates, including man, and (c) molecular tools and resources for functional analysis of galectins in the zebrafish model that will be shared with the scientific community.