Genetic Susceptibility to the Murine Model of Retinopathy of Prematurity: Identification of a Novel Role of Tyrosinase in Retinal Angiogenic Regulation

Abstract

Retinopathy of Prematurity (ROP) is a major cause of vision loss in the pediatric population. A growing body of evidence suggests that a heritable component contributes to risk of disease development. Identification of genes that modify disease susceptibility may provide a means to determine which children are at higher risk of developing ROP, as well as identify potential pharmacological targets to prevent progression of disease to vision-threatening stages. Using the murine model of ROP, oxygen-induced retinopathy (OIR), we developed a mapping cross that identified 2 quantitative trait loci associated with resistance to OIR. This work also found an association between albinism and reduced retinal avascular area. As albinism in our study was caused by loss of function of Tyrosinase (Tyr), we confirmed that function of this gene is associated with increased risk of OIR susceptibility using the Tyr-null murine strain. Tyr function was also found to inhibit endothelial progenitor cell (EPC) proliferation, mobilization, and recruitment to the retina. Subsequent studies exploring the mechanism of these findings demonstrated that Tyr function contributes to peripheral production of dopamine, and that dopamine inhibits retinal revascularization and EPC recruitment to the retina by signaling through the D1-like family of receptors. A time course study examining the number of EPCs in bone marrow, blood, and retina using both Tyr-null and wild-type mice identified patterns of proliferation, mobilization, and recruitment associated with more and less successful response to OIR. This study additionally suggested that retinal revascularization and associated EPC response in this model begins prior to the customary time point of P12, which has important implication for future studies seeking to modify EPC contribution to this disease. A microarray analysis comparing transcriptional regulation between strains of mice known to be susceptible and resistant to OIR identified additional pathways that also contribute to disease susceptibility, and identified several areas of interest for future experiments. Together, these studies describe a novel role of dopaminergic signaling in retinal vascularization and identify potential mechanisms that contribute to susceptibility to ROP.