Msx-2 and p21 mediate the pro-apoptotic but not the anti-proliferative effects of BMP4 on cultured sympathetic neuroblasts.
The differentiation, survival, and proliferation of developing sympathetic neuroblasts are all coordinately promoted by neurotrophins. In this study, we demonstrate that bone morphogenetic protein 4 (BMP4), a factor known to be necessary for the differentiation of sympathetic neurons (Schneider et al., 1999), conversely reduces both survival and proliferation of cultured E14 sympathetic neuroblasts. The anti-proliferative effects of BMP4 occur more rapidly than the pro-apoptotic actions and appear to involve different intracellular mechanisms. BMP4 treatment induces expression of the transcription factor Msx-2 and the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21). Treatment of cells with oligonucleotides antisense to either of these genes prevents cell death after BMP4 treatment but does not significantly alter the anti-proliferative effects. Thus Msx-2 and p21 are necessary for BMP4-mediated cell death but not for promotion of exit from cell cycle. Although treatment of cultured E14 sympathetic neuroblasts with neurotrophins alone did not alter cell numbers, BMP4-induced cell death was prevented by co-treatment with either neurotrophin-3 (NT-3) or nerve growth factor (NGF). This suggests that BMP4 may also induce dependence of the cells on neurotrophins for survival. Thus, sympathetic neuron numbers may be determined in part by factors that inhibit the proliferation and survival of neuroblasts and make them dependent upon exogenous factors for survival.
Gomes
W A
WA
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Kessler
J A
JA
D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D018398:Homeodomain Proteins; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D020932:Nerve Growth Factor / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects*; D051028:bcl-2-Associated X Protein
C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C084119:MSX2 protein; D020933:Neurotrophin 3; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020932:Nerve Growth Factor