The primary object of this proposal is to determine the roles of two polysialyltransferases, PST and STX, in polysialic acid formation and the roles of polysialic acid and HNK-1glycan in development and neural tumor malignancy. First, we discovered that PST and STX synergistically polysialylate NCAM. Second, we discovered that glioma cell invasion is facilitated by polysialic acid, while gene abrogation of STX results in anomalies in hippocampal formation and cerebellar cortex neuron development. Third, we have cloned cDNA encoding HNK-1 glycan-forming sulfotransferase (HNK-1ST), which can form HNK-1 glycan on NCAM. Based on these findings, three major areas of further study are proposed as follows. 1. Determining the roles of two polysialyltransferases, PST and STX, in the formation of polysialic acid. We will determine how PST and STX synergistically polysialylate NCAM and whether polysialylation and HNK-1 glycan formation, compete with each other. 2. Determining the roles of polysialic acid in development. We will determine whether abrogation of the PST and/or STX genes or their overexpression in transgenic mice results in an anomaly in neural development. 3. Determining the roles of polysialic acid and HNK-1 glycan in tumor invasion and metastasis. We will determine the roles of polysialic acid and HNK-1 glycan in tumor invasion and metastasis using various mice that have defective NCAM, MAG, or PST/STX gene. These studies will allow us to determine the roles of polysialic acid under physiological and pathophysiological conditions.
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