The Role of the Microglial Cx3crl Pathway in the Postnatal Maturation of Retinal Photoreceptors

Microglia are the resident immune cells of the CNS, and their response to infection, injury and disease is well documented. More recently, microglia have been shown to play a role in normal CNS development, with the fractalkine-Cx3crl signaling pathway of particular importance. This work describes the interaction between the light-sensitive photoreceptors and microglia during eye opening, a time of postnatal photoreceptor maturation. Genetic removal of Cx3crl (Cx3crl(GFP/GFP))led to an early retinal dysfunction soon after eye opening [postnatal day 17 (PI 7)] and cone photoreceptor loss (P30 onward) in mice of either sex. This dysfunction occurred at a time when fractalkine expression was predominantly outer retinal, when there was an increased microglial presence near the photoreceptor layer and increased microglial-cone photoreceptor contacts. Photoreceptor maturation and outer segment elongation was coincident with increased opsin photopigment expression in wild-type retina, while this was aberrant in the Cx3crl(GFP/GFP) retina and outer segment length was reduced. A beadchip array highlighted Cx3crl regulation of genes involved in the photoreceptor cilium, a key structure that is important for outer segment elongation. This was confirmed with quantitative PGR with specific c ilium-related genes, Rpgr and Rpgripl, downregulated at eye opening (P14). While the overall cilium structure was unaffected, expression of Rpgr, R-pgripl, and centrin were restricted to more proximal regions of the transitional zone. This study highlighted a novel role for microglia in postnatal neuronal development within the retina, with loss of fractalkine-Cx3crl signaling leading to an altered distribution of cilium proteins, failure of outer segment elongation and ultimately cone photoreceptor loss.