L-fucose, a 6-deoxy monosaccharide widely distributed in vertebrate organisms, is a determinant of many functional glycans that play central roles in numerous physiological processes, including angiogenesis, fertilization and neuronal development. Aberrant fucosylation is associated with developmental disorders, cancer and inflammation. GDP-fucose (GDP-Fuc), the universal fucosyl donor, serves as the substrate for fucosyltransferases, enzymes located in the endoplasmic reticulum and Golgi, that transfer fucose from the GDP-Fuc donor to N- and O-linked glycans, and to protein acceptors, such as Notch and its ligands, directly. We discovered that GDP-Fuc analogs served as powerful tools to modulate the Notch signaling activity and motor neuron migration in zebrafish embryos. Using two transgenic zebrafish lines, in which either a Notch responsive element or motor neurons are labeled with green fluorescent protein, the impact of these unnatural sugars on Notch signaling or motor neuron migration can be visualized. We found that the nucleotide sugar analogs with slightly different chemical structures could have dramatically different impact on these processes. Unnatural fucose analogs were incorporated into epidermal growth factor-like (EGF) repeats of receptor proteins with different efficiency by protein O-fucosyltransferase 1. The molecular mechanism underlining these processes was investigated in parallel using in vitro biochemical assays.

Chemical tools for imaging and probing Notch signaling and neuronal development in zebrafish embryos

247th National Meeting (2014)

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