Ras activation in retinal progenitor cells induces tumor formation in the eye

The RAS gene family members, H-RAS, K-RAS, and N-RAS, are frequently mutated in human cancer. A subset of retinal tumors displays K-RAS mutations; however, the specific role of RAS activation on retinal tumor formation is unclear. To examine the role of RAS in retinal development, we overexpressed the mutant H-RAS gene (G12V) in retinal progenitor cells (RPCs), a multipotent progenitor cell population that gives rise to all six neuron types in the retina and to the Muller glia. The Msi1^CreER mouse strain was used to induce mosaic activation of Ras (RasV12) in the RPCs of the postnatal retina. RAS-activated RPCs translocated to the basal part of the retina, differentiated into cells with glial characteristics, and underwent apoptosis. We next induced RAS activation in a large population of RPCs in the embryonic retina using the Pax6^Cre mouse strain. In contrast to the phenotype observed in Msi1^CreER;RasV12 mice, Ras-activated cells retained their apical attachment. Basal translocation was partially suppressed in the retina of Pax6^Cre;RasV12 mice, indicating that basal translocation of Ras-activated cells was not cell autonomous. Notably, RAS-activated retinal cells were highly proliferative and promoted the formation of eye tumors in Pax6^Cre;RasV12 mice. Together, our data indicate that the tumorigenicity of RAS activation in RPCs is context dependent, with tumor formation occurring when RAS activity is present in a large cluster of embryonic RPCs.