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 bone morphogenetic proteins (BMPs) in inducing apoptosis of MAH cells, an immortalized sympathoadrenal progenitor cell line. Treatment of MAH cells with BMP2 or BMP4 killed the cells in a dose-dependent manner. By contrast, treatment with BMP7 or TGFbeta1 failed to affect survival, suggesting that induction of apoptosis is specific to the dpp subgroup of BMPs. Survival after treatment with BMP2 or BMP4 required addition of fibroblast growth factor (FGF) and nerve growth factor (NGF), indicating that BMP treatment made the neurons dependent upon an exogenous factor for survival. Several experimental observations suggested an apoptotic mechanism for BMP-induced death. After BMP2 treatment, the cells progressively shrank and became pyknotic. Further, there was prominent endonucleosomic cleavage of DNA (laddering) as well as TUNEL staining. Moreover, BMP-induced death was inhibited by the caspase inhibitor z-VAD and was partially prevented by the endonuclease inhibitor aurintricarboxylic acid. These observations suggest that neuron numbers may be regulated by factors which promote death and that exposure to such factors may be a signal for the development of dependence upon other growth factors for survival.
Song
Q
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Department of Neurology, Albert Einstein College of Medicine, Kennedy Center Room 901, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Mehler
M F
MF
Kessler
J A
JA
D000311:Adrenal Glands / Q000294:innervation*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000196:embryology; D016212:Transforming Growth Factor beta
D000590:Amino Acid Chloromethyl Ketones; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D015853:Cysteine Proteinase Inhibitors; D006133:Growth Substances; D009414:Nerve Growth Factors; D019384:Nucleic Acid Synthesis Inhibitors; D016212:Transforming Growth Factor beta; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016222:Fibroblast Growth Factor 2; D001312:Aurintricarboxylic Acid