Novel Mouse Models to Understand ST6Gal1-Mediated Sialylation Effects in the Developing and Pathologic Brain

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PROJECT SUMMARY/ABSTRACT Neurodevelopment requires the controlled self-renewal and differentiation of neural stem cells. Dysregulation of neural stem cell-related pathways occurs in many neuropathologies, even when the direction of change or genetic alterations are distinct. We find that normal and neoplastic neural stem cells express ST6Gal1, the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the cell surface. There are critical gaps in our understanding of how ST6Gal1-mediated sialylation could impact cell signaling to regulate neurodevelopment, brain aging, neurodegeneration, or gliomagenesis. To fill these gaps and further investigate the function and molecular targets of ST6Gal1 and a2,6 sialylation in the brain, we generated two novel mouse models that permit spatial and temporal elevation of ST6Gal1 in astrocytes and neural stem cells. We seek to characterize the expression of ST6Gal1 in the existing mouse models over time and determine effects of ST6Gal1-mediated a2,6 sialylation on the normal and neoplastic neural stem cell pool in vivo. In the short-term, these studies will elucidate impacts of ST6Gal1 and sialylation in the developing brain and in gliomagenesis. Once characterized, the unique models will be a valuable resource for the neuroscience and neuro-oncology communities to identify neuropathological roles for ST6Gal1- mediated a2,6 sialylation.