Neurotrophin-3: a Neurotrophic Factor Related to NGF and BDNF
Peter C. MaisonpierreLeonardo BelluscioStephen P. SquintoNancy Y. IpMark E. FurthRonald M. LindsayGeorge D. Yancopoulos
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Abstract:
The development and maintenance of the nervous system depends on proteins known as neurotrophic factors. Although the prototypical neurotrophic factor, nerve growth factor (NGF), has been intensively studied for decades, the discovery and characterization of additional such factors has been impeded by their low abundance. Sequence homologies between NGF and the recently cloned brain-derived neurotrophic factor (BDNF) were used to design a strategy that has now resulted in the cloning of a gene encoding a novel neurotrophic factor, termed neurotrophin-3 (NT-3). The distribution of NT-3 messenger RNA and its biological activity on a variety of neuronal populations clearly distinguish NT-3 from NGF and BDNF, and provide compelling evidence that NT-3 is an authentic neurotrophic factor that has its own characteristic role in vivo.Keywords:
Ciliary neurotrophic factor
Neurotrophin-3
Background: Neurotrophins like brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neuroprotective and prevent cell death during ischemic conditions. BDNF and NGF expression have been shown to increase after hypoxia in animal studies. However, the effect of hypoxia on systemic release of BDNF and NGF in vivo has not been thoroughly studied. We investigated the impact of acute hypoxia on plasma concentrations of BDNF and NGF in healthy men.
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在哺乳动物的大脑，四 neurotrophins 被识别了：神经生长因素(NGF ) ，导出大脑的神经营养的因素(BDNF ) ， neurotrophin-3 (NT-3 ) 和 neurotrophin-4/5 (NT-4/5 ) 。NGF 在中央、外部的神经系统的开发和函数施加一个重要角色。然而，有免疫力的房间的几种类型例如桅杆房间，淋巴细胞， basophils 和嗜曙红血球，生产，存储并且释放 NGF，这最近被记录了。积累现出症状之前的潜、临床的数据显示 NGF 和另外的 neurotrophins 的机能障碍可以贡献损害有免疫力的回答， NGF 的集中经常与疾病严厉相关。因此，这研究的目的是阐明贡献的 cytokineneurotrophins 相互作用的潜在的发信号机制增加了 NGF 层次。我们抄写 factorNF-B 玩的数据表演在调整 B-cell-derived NGF 的一个枢轴的角色表示。
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The peripheral nervous system retains a considerable capacity for regeneration. However, functional recovery rarely returns to the preinjury level no matter how accurate the nerve repair is, and the more proximal the injury the worse the recovery. Among a variety of approaches being used to enhance peripheral nerve regeneration are the manipulation of Schwann cells and the use of neurotrophic factors. Such factors include, first, nerve growth factor (NGF) and the other recently identified members of the neurotrophin family, namely, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5); second, the neurokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF); and third, the transforming growth factors (TGFs)-β and their distant relative, glial cell line–derived neurotrophic factor (GDNF). In this review article we focus on the roles in peripheral nerve regeneration of Schwann cells and of the neurotrophin family, CNTF and GDNF, and the relationship between these. Finally, we discuss what remains to be understood about the possible clinical use of neurotrophic factors. © 1998 Wiley-Liss, Inc. MICROSURGERY 18:397–405, 1998
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During the development period, neurons are abundantly generated in the vertebrate nervous system. Following the arrival of their axons in the target areas, only a proportion of these neurons will survive. These neurons are thought to have successfully competed for a target-derived, retrogradely transported neurotrophic factor, present in limited amounts in the target fields. Such a neurotrophic factor, in its narrow definition, is a survival factor for embryonic neurons in either the peripheral or central nervous system. This definition is derived from research on nerve growth factor (NGF) (Levi-Montalcini and Booker, 1960). NGF belongs to the family of "neurotrophic," which subsumes brain-derived neurotrophic factor (BDNF; for reviews, see Barde, 1989; Levi-Montalcini, 1987; Thoenen et al., 1987), neurotrophin-3/neurotrophin 4 (NT-3/NT-4; see Glass et al., 1991; Hohn et al, 1990), and neurotrophin 5 (NT-5; see Berkemeier et al., 1991). In addition, a number of other nontarget-derived molecules are known to influence survival and differentiation of certain neurons and nonneuronal cells. These factors include ciliary neurotrophic factor (CNTF), acidic and basic fibroblast growth factor (FG F-1 and FGF-2, respectively), epidermal growth factor (EGF), insulin-like growth factors I and II (IGF-I, IGF-II), and muscle-derived differentiation factor (MDF).
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We used compartmented cultures to study the regulation of adult sensory neurite growth by neurotrophins. We examined the effects of the neurotrophins nerve growth factor (NGF), neurotrophin-3 (NT3), and BDNF on distal neurite elongation from adult rat dorsal root ganglion (DRG) neurons. Neurons were plated in the center compartments of three-chambered dishes in the absence of neurotrophin, and neurite extension into the distal (side) compartments containing NGF, BDNF, or NT3 was quantitated. Initial proximal neurite growth did not require any of the neurotrophins, while subsequent elongation into distal compartments required NGF. After neurites had extended into NGF-containing distal compartments, removal of NGF by treatment with anti-NGF resulted in the cessation of growth with minimal neurite retraction. In contrast to the effects of NGF, no distal neurite elongation was observed into compartments with BDNF or NT3. To examine possible additive influences, neurite extension into compartments containing BDNF plus NGF or NT3 plus NGF was quantitated. There was no increased neurite extension into NGF plus NT3 compartments, while the combination of BDNF plus NGF resulted in an inhibition of neurite extension compared with NGF alone. We then investigated whether the regrowth of neurites that had originally grown into NGF subsequent to in vitro axotomy still required NGF. The results demonstrated that unlike adult sensory nerve regeneration in vivo, the in vitro regrowth did require NGF, and neither BDNF nor NT3 was able to substitute for NGF. Since the initial growth from neurons after dissociation (which is also a regenerative response) did not require NGF, it would appear that neuritic growth and regrowth of adult DRG neurons in vitro includes both NGF-independent and NGF-dependent components. The compartmented culture system provides a unique model to further study aspects of this differential regulation of neurite growth. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 395–410, 1997
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