Balance of pro-apoptotic TGF-ß and anti-apoptotic insulin effects in the control of cell death in the postnatal mouse retina

Abstract

Transforming growth factor (TGF)-β and insulin display opposite effects in regulating programmed cell death during vertebrate retina development; the former induces apoptosis while the latter prevents it. In the present study we investigated coordinated actions of TGF-β and insulin in an organotypic culture system of early postnatal mouse retina. Addition of exogenous TGF-β resulted in a significant increase in cell death whereas exogenous insulin attenuated apoptosis and was capable of blocking TGF-β-induced apoptosis. This effect appeared to be modulated via insulin-induced transcriptional down-regulation of TGF-β receptor II levels. The analysis of downstream signalling molecules also revealed opposite effects of both factors; insulin provided survival signalling by increasing the level of anti-apoptotic Bcl-2 protein expression and phosphorylation and down-regulating caspase 3 activity whereas pro-apoptotic TGF-β signalling reduced Bcl-2 mRNA levels and Bcl-2 phosphorylation and induced the expression of TGF-induced immediate-early gene (TIEG), a Krüppel-like zinc-finger transcription factor, mimicking TGF-β activity