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

Abstract

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 Msi1CreER 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 Pax6Cre mouse strain. In contrast to the phenotype observed in Msi1CreER;RasV12 mice, Ras-activated cells retained their apical attachment. Basal translocation was partially suppressed in the retina of Pax6Cre;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 Pax6Cre;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.