The expression of gangliosides in the nervous system is not only cell specific and developmentally regulated, but also closely related to the differentiation state of the cell. These molecules are known to play important modulatory roles in cellular recognition, interaction, adhesion, and signal transduction during specific developmental stages. We hypothesize that the temporal and spatial expression of gangliosides in the nervous system is closely related to their metabolism, in particular, biosynthesis.
Four specific aims are proposed to test this hypothesis. (1) We will carry out detailed structural studies on many stage-specific gangliosides which play crucial roles in the early development of the nervous system. These structural studies are fundamental for all molecular biological investigationson the biosynthesis of these molecules. (2) Because one of the regulatory mechanisms occurs at the transcriptional level, we will focus on cloning the gene encoding the first sialyltransferase (GM3-synthase) that gates the synthesis of gangliosides; this has never been achieved. (3) We will elucidate the promotor sequences of the genes encoding several key regulatory sialyltransferases and to study their structure. Analysis of the transcription factors for ganglioside synthesis has never been achieved, but would be crucial for understanding the cell-specific and development-regulated regulation of the genes in this process. (4) As evidence has been provided that the activities of several glycoslytransferases can be modified post-translationally, e.g., by phosphorylation and N-glycosylation, we will elucidate the role of phosphorylation/dephosphorylation as a mechanism for the fast and reversible regulation of glycosyltransferase activities in response to physiological demands. The role of N-glycosylation will also be explored with respect to the activity and cellular localization/trafficking of these enzymes in the cell, employing the molecular biological knowledge gained above. An understanding of the molecular mechanisms underlying the differential expression of cell surface gangliosides should greatly enrich our knowledge in their functions in normal brain development as well as in neurological disorders that result in mental retardation.
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