Fred Hagen, Ph.D.

We study glycosylation because multi-cellular organisms have evolved hundreds of gene products that are involved in post-translational modification of the cell surface. Cell surface molecules mediate cell-cell interactions, signaling events and structures that are important for development of tissues and organs. Defects in the post-translational modification machinery result in severe inherited disorders. The most prevalent class of cell-surface molecules are glycoconjugates, which are proteins, lipids or carbohydrates that are modified with sugar chains (oligosaccharides). In mass terms, the saccharide component of a glycoprotein can account for up to 85% of its molecular weight. In terms of complexity, literally millions of different complex carbohydrate side chains can be synthesized, and these are expressed in tissue-specific patterns throughout development.

The role of carbohydrate chain modification in development, however, has not been closely examined for hundreds of glycosyltransferase genes. For this reason the study of glycosylation in development is in its infancy. We hypothesize that many different classes of oligosaccharides on the cell surface are crucial for orchestrating development processes because many unique glycoconjugate structures are expressed in specific temporal and spatial patterns throughout development.

A Comprehensive Functional Genomics Screen of Glycosyltransferases. Our objective is to identify every member of the glycosyltransferase superfamily, using motif modeling and searching strategies. Each of these glycosyltransferases will be cloned and targeted in a reverse genetic screen to identify those glycosyltransferases that are critical for development. We believe that C. elegans is best suited for a comprehensive genomics approach because it is a very simple organism, composed of about 1000 somatic cells, in which the complete cell lineage is known at single cell resolution. Furthermore, C. elegans is amenable to genetic manipulation and rapid RNA interference screens. These features will allow us to screen each glycosyltransferase gene for a loss-of-function phenotype. Those glycosyltransferases that are critical of development will then be characterized biochemically and structurally so that we can work on the interface of biology and biochemistry to elucidate important novel mechanisms in development.