Transforming growth factor-beta induced cell death in the developing chick retina is mediated via activation of c-jun N-terminal kinase and downregulation of the anti-apoptotic protein Bcl-X(L)

Abstract

Cell death in general and especially in neuronal cells is regulated by a complex interplay between survival and death signals, generated by extracellular factors like neurotrophins and intracellular regulation mechanisms. The pleiotrophic transforming growth factor beta (TGF-beta) influences life and death decisions in cells depending on cell type and other growth factors present. It has been previously shown that TGF-beta is necessary to induce ontogenetic cell death during retinal development. In the present study, we analyzed the underlying intracellular signaling processes involved in TGF-beta mediated cell death. We established a cell culture system mimicking the situation of ontogenetic cell death in vivo with cultured retinal cells isolated from the retinae of embryonic day 7 white leghorn chick embryos. The neutralization of TGF-beta inhibits cell death of cultured retinal cells whereas exogenous application of TGF-beta is followed by enhanced apoptosis as observed by in situ cell death detection (terminal deoxynucleotidyl transferase-mediated nick end labeling) assay. TGF-beta induces the activation of c-jun N-terminal kinase in the mitogen-activated protein kinase (MAP kinase) pathway and provokes downregulation of the anti-apoptotic BCL-X(L) protein. Thus, TGF-beta influences cell death via activation of a pro-apoptotic MAP-kinase cascade accompanied by a downregulation of anti-apoptotic signals.