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S. Bhattacharya, K. Mallya, I. Ahmad; Neuronal versus Glial Differentiation of Late Retinal Stem Cells/Progenitors: Signal Transduction Pathways Underlying the Biphasic Effects of CNTF . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3244.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: CNTF, among the known factors, has emerged as an important regulator of differentiation during late retinal histogenesis. We have previously shown that signaling mediated by CNTF may act as a molecular switch that regulates the differentiation of late retinal stem cells/progenitors into neurons and glia. In this report, we have examined the CNTF–mediated signal transduction pathways underlying the molecular switch Methods: Late retinal stem cells/progenitors, enriched as neurospheres, were cultured in different concentrations of CNTF for 4–5 days and expression of markers of specific retinal cell types were analyzed by immunocytochemical and RT–PCR analyses. To examine the relative activation of specific CNTF–mediated pathways, i.e. JAK–STAT and MAP kinase pathways, the state of phosphorylations of STAT3 and ERK1/2, in response to different concentrations of CNTF and in the presence of specific inhibitors of the pathways was analyzed. Results: CNTF had a concentration dependent effect on the differentiation of late retinal stem cells/progenitors. Exposure of retinal stem cells/progenitors to a low concentration of CNTF (50 ng/ml), that promotes neuronal differentiation, led to a preferential phosphorylation of ERK1/2 suggesting the involvement of MAPK pathway. In contrast, exposure to a high concentration of CNTF (100 ng/ml), that promotes glial differentiation, preferentially phosphorylated STAT3, suggesting the involvement of JAK–STAT pathway. Conclusions: The biphasic effects of CNTF on neuronal versus glial differentiation of late retinal stem cells/progenitors are likely due to a concentration dependent–activation of specific intracellular signaling pathways. Such a mechanism will allow a differential response of retinal stem cells/progenitors to the changing milieu, towards determining the efficiency of differentiation, in terms of cell types and their numbers.
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