Tightly regulation of polysialyltransferase ST8SiaII/STX expression is required for early hippocampal neuron development

MARCELA ADRIANA BROCCO; FRASCH, A. C.

Washington

Congreso; Society for Neuroscience; 2005

Polysialic acid (PSA) attached to NCAM is involved in cell-cell interactions participating in structural and functional plasticity of neuronal circuits. Two polysialyltransferases ST8SiaII/STX and ST8SiaIV/PST are responsible enzymes for NCAM polysialylation. We previously showed that PSA expression parallels ST8SiaII/STX  mRNA levels during hippocampus development. We also showed taht ST8SiaII/STX overexpression in promary hippocampal cultures induces neuronal death. Neuronal death of primary cultures could be prevented by mutations that disrupted the ST8SiaII/STX 3-dimentional structure. Cell death is related to ST8SiaII/STX autopolysialylation because overexpression of a ST8SiaII/STX devoid of PSA prevented neuronal death. ST8SiaII/STX overexpression at different cultures days resulted in a survival curve. At initial stages (1-4 days culture) expression induced cell death, but cells survived when transfections were done at 11-14 days in vitro. Interestingly, cell death was observed before synaptogenesis; while neurons that have already established synapsis were not affected by ST8SiaII/STX  overexpression. In good agreement, we found that ST8SiaII/STX RNA interference (RNAi) resulted in PSA absence from neuronal surfaces. These interfered cells showed an inhibited neuritic growth that was accompanied by a down-regulation of GAP-43 expression- a marker for elongating axons- and a lower density of synaptophysin clusters. Overall, our results indicate that ST8SiaII/STX is involved in process development at initial stages of hippocampus ontogeny. Thus, ST8SiaII/STX overexpression results in cell death because of ST8SiaII/STX  autopolysialylation and ST8SiaII/STX  depletion induces a limited neuronal development due to PSA absence. Bothe results explain why ST8SiaII/STX expression should be tightly regulated sprecially at a temporal window to avoid cell death andt to allow neuritic development.