Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons.
Large numbers of neurons are eliminated by apoptosis during nervous system development. For instance, in the mouse dorsal root ganglion (DRG), the highest incidence of cell death occurs between embryonic days 12 and 14 (E12-E14). While the cause of cell death and its biological significance in the nervous system is not entirely understood, it is generally believed that limiting quantities of neurotrophins are responsible for neuronal death. Between E12 and E14, developing DRG neurons pass through tissues expressing high levels of axonal guidance molecules such as Semaphorin 3A (Sema3A) while navigating to their targets. Here, we demonstrate that Sema3A acts as a death-inducing molecule in neurotrophin-3 (NT-3)-, brain-derived neurotrophic factor (BDNF)- and nerve growth factor (NGF)-dependent E12 and E13 cultured DRG neurons. We show that Sema3A most probably induces cell death through activation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway, and that this cell death is blocked by a moderate increase in NGF concentration. Interestingly, increasing concentrations of other neurotrophic factors, such as NT-3 or BDNF, do not elicit similar effects. Our data suggest that the number of DRG neurons is determined by a fine balance between neurotrophins and Semaphorin 3A, and not only by neurotrophin levels.
Ben-Zvi
Ayal
A
Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
Yagil
Zohar
Z
Hagalili
Yamit
Y
Klein
Hagit
H
Lerman
Omer
O
Behar
Oded
O
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology*; D020439:Growth Cones / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D020933:Neurotrophin 3 / Q000008:administration & dosage / Q000494:pharmacology; D020800:Receptor, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics; D040121:Semaphorin-3A / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction
D000873:Anthracenes; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D040121:Semaphorin-3A; C432165:pyrazolanthrone; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases