NEW HORIZON OF NEURON-ASTROCYTE INTERACTION : NEUROTROPHICACTIVITY OF L-SERINE

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The overall aim of the project was to determine the physiological significance of astrocyte-derived L-Ser on the surival and development of CNS neurons in vivo. The hypothesis to be tested is that astrocyte-specific expression of 3PGDH, an enzyme catalyzing the initial step, of L-Ser biosynthesis in animal cells, is the molecular mechanism underlying neurotrophic action of L-Ser on CNS neurons. In the project, we set our effort to understand the molecular basis of astrocyte-specific expression of 3PGDH gene. We first isolated and sequenced a BAC clone which contains the mouse 3PGDH gene. Based on this structural information, we then examined promoter activity of the gene. We found using a reporter gene assay system that I.8 kb region upstream from the initiation codon in the 5'-flanking sequence directs high-level expression of reporter in astrocytes. We are now trying to identify sequence responsible for astrocyte-specific transcriptional activation by deletion of this region. In parallel with this promoter analysis, our effort was also directed to establish transgenic mice with ectopic expression of 3PGDH cDNA in CNS neurons. We constructed the transgene in which rat 3pGDH cDNA could be expressed under the control of neuron-specific promoter, Founder mice were recently obtained and we are now selecting lines with high-level neuronal expression of the cDNA. We believe that these transgenic mice will be a useful tool for testing our hypothesis.