Roles of glycosyltransferases in drosophila development

It is surprising that there are only about 80 described congenital diseases that result from mutations in any of the 1% of genes in the human genome (~200-250 genes) dedicated to protein glycosylation. It is these glycosylation events that provide tremendous protein diversity and contribute to proper protein folding, function, and subcellular localization. Thus, the rarity with which human congenital disorders of glycosylation (CDGs) are observed despite the myriad of genes involved in this process and the apparent critical role for proper protein form and function suggests that glycosylation is critical for proper development. However, the role of glycans in development has been largely understudied and there are only a few genetic models of human CDGs in existence. Glycosylation occurs by the enzymatic addition of sugar-derived molecules and is estimated to provide 10-104 times more diversity than the unmodified proteome alone. Glycans are present on the surface of nearly every cell within multicellular organisms and are capable of facilitating communication with the cell and its environment and with other cells and also have structural roles as critical components of extracellular matrix. However, the complexity of glycan formation makes it difficult to understand the diverse and pleiotropic roles glycans play in cellular biology. The utility of Drosophila to elucidate the role of glycans in development as well as disease has only been appreciated recently. Herein, I further demonstrate the utility of Drosophila to understand the roles of both N- and O-glycans in development and cell signaling. Furthermore, I utilize the fly to understand the biology of glycans in a human disorder of congenital disease, Peters Plus Syndrome. I demonstrate that the previously reported Dpp signal antagonism achieved by the sugar derivative UDP-N-Acetyglucosamine (GlcNAc) is carried out by the synthesis of a chondroitin-sulfate sink produced in the embryonic cardiac mesoderm and by the addition of GlcNAc to the type I receptor Saxophone to limit Dpp signal through Tkv exclusively. Furthermore, loss of the Drosophila ortholog of the human B3GLCT gene, sugarcoated, demonstrates a critical role for O-linked mucins in cell hypertrophic growth during larval development and oogenesis and demonstrates a potential role for human mucins in chondrocyte hypertrophy-an event required for the majority of human bone growth-and a potential mechanistic reason for growth defects observed in Peters Plus Syndrome patients.