Müller cells, the primary macroglia of the retina, support various functions of retinal ganglion cells (RGCs). Here, we demonstrate a nucleotide‐mediated communication between these two types of cells, by which Müller cells control neurite outgrowth of RGCs by activation of P2 receptors such as P2Y₆. Cultured mouse RGCs had significantly enhanced neurite outgrowth when cultured with either cultured mouse Müller cells or conditioned medium derived from Müller cells, and this was completely inhibited by the nucleotide‐degrading enzyme, apyrase. This increase in outgrowth was mimicked by exogenously applied nucleotides such as ATP, uridine triphosphate, and uridine diphosphate. Pharmacological and genetic analysis revealed that P2Y₆ receptor in RGCs was responsible for the increased neurite outgrowth. P2Y₆ receptor was expressed in the ganglion cell layer of the retina and in RGC primary cultures. High performance liquid chromatography has revealed that Müller cells constitutively release uridine triphosphate, which is immediately metabolized into uridine diphosphate, an endogenous agonist for P2Y₆ receptor. In the in vitro ocular hypertension model (i.e., glaucoma model), neurite outgrowth in RGCs was significantly reduced, which was associated with a decrease in P2Y₆ receptors. Taken together, Müller cells control neurite outgrowth of RGCs by activating P2 receptors such as P2Y₆ receptor, and the receptor expression level might be down‐regulated in glaucoma.

Müller cells support various functions of retina including those of retinal ganglion cells (RGCs). Here, we report an importance of nucleotide‐mediated communication between these two types of cells. Müller cells were found to release uridine diphosphate (UTD), uridine triphosphate (UTP), and activate P2Y6 receptors in RGCs, which was essential for neurite outgrowth of RGCs. In addition, P2Y₆ receptors in RGCs were reduced in a glaucoma model in vitro, suggesting an involvement of their dysfunction in the pathogenesis of glaucoma.