Abstract W P91: Regulating Set-ß’s Subcellular Localization Toggles Its Function Between Inhibiting and Promoting Axon Growth and Regeneration

Abstract

The failure of the adult mammalian central nervous system (CNS) neurons to regenerate axons after stroke remains a major problem. Manipulation of various cell-autonomous factors along with overcoming the inhibitory adult CNS environment only partially restores regeneration. Transcriptional regulators like Set-β are well-positioned to regulate intrinsic axon regeneration capacity, which declines developmentally in maturing CNS neurons. Set-β also functions at the cellular membranes and its subcellular localization is disrupted in Alzheimer’s disease, but many of its biological mechanisms have not been explored in neurons. We found that Set-β was upregulated postnatally in CNS neurons. Remarkably, nuclear Set-β suppressed whereas Set-β localized to cytoplasmic membranes promoted neurite growth in primary CNS neurons. Furthermore, mimicking serine 9 phosphorylation blocked the ability of nuclear Set-β to suppress neurite growth. Finally, recruitment of Set-β to cellular membranes through gene therapy promoted optic nerve axons regeneration in vivo. Thus, Set-β differently regulates axon growth and regeneration depending on subcellular localization and phosphorylation, suggesting a novel mode of regulation of cellular behavior through disparate activities in different cellular compartments, which could be clinically relevant for treating stroke injury in CNS.