Muller cell-mediated neurite outgrowth of the retinal ganglion cells via P2Y(6) receptor signals

摘要

Muller 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 Muller cells control neurite outgrowth of RGCs by activation of P2 receptors such as P2Y(6). Cultured mouse RGCs had significantly enhanced neurite outgrowth when cultured with either cultured mouse Muller cells or conditioned medium derived from Muller 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 P2Y(6) receptor in RGCs was responsible for the increased neurite outgrowth. P2Y(6) receptor was expressed in the ganglion cell layer of the retina and in RGC primary cultures. High performance liquid chromatography has revealed that Muller cells constitutively release uridine triphosphate, which is immediately metabolized into uridine diphosphate, an endogenous agonist for P2Y(6) receptor. In the invitro ocular hypertension model (i.e., glaucoma model), neurite outgrowth in RGCs was significantly reduced, which was associated with a decrease in P2Y(6) receptors. Taken together, Muller cells control neurite outgrowth of RGCs by activating P2 receptors such as P2Y(6) receptor, and the receptor expression level might be down-regulated in glaucoma.