BONE MORPHOGENETIC PROTEINS INDUCE APOPTOSIS AND GROWTH-FACTOR DEPENDENCE OF CULTURED SYMPATHOADRENAL PROGENITOR CELLS

Neuron numbers in developing vertebrate organisms are regulated by the availability of growth factors which promote their survival. However, neuron survival may also be regulated by growth factors which promote rather than prevent cell death. This study examined the effects of bo ne morphogenetic proteins (BMPs) in inducing apoptosis of MAH cells, a n immortalized sympathoadrenal progenitor cell line. Treatment of MAH cells with BMP2 or BMP4 killed the cells in a dose-dependent manner. B y contrast, treatment with BMP7 or TGF beta 1 failed to affect surviva l, suggesting that induction of apoptosis is specific to the dpp subgr oup of BMPs. Survival after treatment with BMP2 or BMP4 required addit ion of fibroblast growth factor (FGF) and nerve growth factor (NGF), i ndicating that BMP treatment made the neurons dependent upon an exogen ous factor for survival. Several experimental observations suggested a n apoptotic mechanism for BMP-induced death. After BMP2 treatment, the cells progressively shrank and became pyknotic. Further, there was pr ominent endonucleosomic cleavage of DNA (laddering) as well as TUNEL s taining. Moreover, BMP-induced death was inhibited by the caspase inhi bitor z-VAD and was partially prevented by the endonuclease inhibitor aurintricarboxylic acid. These observations suggest that neuron number s may be regulated by factors which promote death and that exposure to such factors may be a signal for the development of dependence upon o ther growth factors for survival. (C) 1998 Academic Press.