Sphingosine-1-Phosphate Receptor 1 Regulates Competition Dependent Astrocyte Morphogenesis and Tiling in Murine Cortex.

Astrocytes are highly abundant in the mammalian brain and coordinate with neurons and other glial cells to regulate neural circuit structure, function, and blood-brain barrier integrity among many to maintain proper brain homeostasis. Astrocytes perform most of these functions owing to their highly complex morphologies and hundreds of thousands of fine processes that are important in contacting neuronal synapses and other glial cells. In fact, the morphological complexity of astrocytes is regulated by the presence and activity of neurons and helps establish astrocyte territory/tiling in a nonoverlapping pattern; however, the mechanisms of astrocyte tiling are not well characterized. Using a human astrocyte-mouse neuron coculture system, we previously showed that sphingosine-1-phosphate receptor 1 (S1PR1) regulates astrocyte morphogenesis in a neuronal contact dependent manner. In this study, we find that S1PR1 regulates astrocyte morphogenesis in vivo. Using astrocyte-specific S1PR1 knockout mouse models and adeno-associated viral labeling methods, we show that S1PR1 is crucial in establishing competition driven astrocyte tiling and morphogenesis in the developing brain. Furthermore, we show that JAK-STAT3 signaling regulates neuronal contact induced expression of S1PR1 in cocultured astrocytes. These studies therefore uncover a lipid signaling receptor as a major regulator of astrocyte morphogenesis and tiling in murine cortical layers.