Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons
Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons
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DOI：
10.1111/j.1471-4159.2005.03580.x
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Behar, O
中科院分区：
文献类型：
--
作者：
Ben-Zvi, A;Yagil, Z;Behar, O
在神经系统发育过程中，大量神经元通过细胞凋亡而被消除。例如，在小鼠背根神经节（DRG）中，细胞死亡的最高发生率发生在胚胎第12天和第14天（E12-E14）之间。虽然细胞死亡的原因及其在神经系统中的生物学意义还不完全清楚，但通常认为，有限数量的神经营养因子是神经元死亡的原因。在E12和E14之间，发育中的DRG神经元穿过表达高水平轴突引导分子如Semaphorin 3A（Sema 3A）的组织，同时导航到它们的靶点。在这里，我们证明了Sema 3A在神经营养素-3（NT-3）、脑源性神经营养因子（BDNF）和神经生长因子（NGF）依赖性E12和E13培养的背根神经节神经元中充当死亡诱导分子。我们表明，Sema 3A最有可能诱导细胞死亡，通过激活c-Jun N-末端激酶（JNK）/c-Jun信号通路，这种细胞死亡被阻止了适度增加的NGF浓度。有趣的是，增加其他神经营养因子的浓度，如NT-3或BDNF，不会引起类似的效果。我们的数据表明，DRG神经元的数量是由神经营养因子和Semaphorin 3A之间的平衡，而不仅仅是由神经营养因子水平。
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.