CHANGES IN EPIDERMAL GROWTH-FACTOR RECEPTOR EXPRESSION AND COMPETENCETO GENERATE GLIA REGULATE TIMING AND CHOICE OF DIFFERENTIATION IN THERETINA

Previous studies demonstrated that the level of epidermal growth facto r receptors (EGF-Rs) expressed by progenitor cells in the newborn (PO) rat retina was limiting for the generation of Muller glial cells but not for proliferation. To determine whether EGF-R signaling biases cel ls to generate a specific cell type or regulates more general processe s during progenitor cell development, we have introduced extra copies of the EGF-R into progenitor cells at earlier stages (E15 and E18), wh en different cell types are produced. We show that progenitor cells in early embryonic retina (E15) normally express lower levels of EGF-Rs than progenitor cells in later retina (E18 and P0). Whereas lower leve ls of stimulation of endogenous and virally transduced EGF-Rs enhanced proliferation, higher levels reduced proliferation, resulting in prem ature differentiation. At E15, very few EGF-R-infected progenitor cell s differentiated prematurely into Muller glial cells, unlike E18 and P 0 cells, even when they were exposed to an older retinal environment. Higher levels of EGF-R-mediated signaling alone therefore do not speci fy a glial fate, indicating that competence to generate glia is tempor ally regulated by additional mechanisms. The differences in EGF-R expr ession observed among retinal progenitor cells at distinct development al stages may instead help to define signaling thresholds which delay or accelerate their differentiation.