Cellular and molecular characterization of early and late retinal stem cells/progenitors: Differential regulation of proliferation and context dependent role of Notch signaling

Retinal stem cells/progenitors that define the evolutionarily conserved early and late stages of retinal histogenesis are known to have distinct competence to give rise to stage-specific retinal cell types. However, the information regarding their innate proliferative behavior and phenotypic potential in terms of generating neurons and glia is lacking. Here we demonstrate that, like their counterparts in other central nervous system (CNS) regions during early and late stages of embryonic development, the early and late retinal stem cells/progenitors display different proliferative response to fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) and bias towards generating neurons or glia. Although the former predominantly generate neurons, the latter are partial towards giving rise to glia. Transcription profiling identified classes of genes that are differentially expressed in early and late retinal stem cells/progenitors in proliferating conditions and suggested that the distinct proliferative response to FGF₂ and EGF is likely due to differential expression of FGF receptor 1 (FGFR1) and EGF receptor (EGFR). However, the proliferative maintenance of retinal stem cells/progenitors is likely to include other signaling pathways such as those mediated by insulin-like growth factors (IGFs) and stem cell factor (SCF). Transcription profiling of early and late retinal stem cells/progenitors in proliferating and differentiating conditions suggested a context dependent role for Notch signaling, which may constitute one of the mechanisms underlying the stage-dependent phenotypic potential of retinal stem cells/progenitors.