Neurotrophins and Their Receptors—Current Concepts and Implications for Neurologic Disease

doi:10.1006/exnr.1993.1087

Experimental Neurology

Volume 121, Issue 2, June 1993, Pages 200-214

https://doi.org/10.1006/exnr.1993.1087 Get rights and content

Abstract

Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 are members of a family of proteins (the neurotrophins) that promote the differentiation, growth, and survival of peripheral and central nervous system neurons. Recently, the trk family of proto-oncogenes has been found to encode signal-transducing receptors for these growth factors. This discovery has important implications for our understanding of the normal function of these factors in the developing and adult nervous system. In this review, we highlight recent advances in neurotrophin research and discuss their relevance to neurologic disease.

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Cited by (196)

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In the developing and adult central nervous system there is a constant need for formation of neuronal networks. Although such networks are established during embryonic development, their full complexity is reached only in the adult. Moreover, brain plasticity and regeneration depend on the constant renewal of neuronal wiring as well as of a supportive glial network. We discuss here the implications of several pertinent examples of NGF, BDNF, NT-3, FGF, GDNF, and IGF in the processes of multipotency maintenance, self-renewal, and differentiation into distinct neural phenotypes. Most of these growth factors function by binding and activating specific receptor tyrosine kinases, which then trigger a cascade of events that specify programs of gene transcription for proliferation, differentiation, cell survival, or apoptosis. Integrative signaling pathways often require activation of more than one receptor type, and some divergent functions exerted by growth and neurotrophic factors can be understood in this context together with the microenvironment in which the activated stem cell is localized.
Pro-domain in precursor nerve growth factor mediates cell death
2012, Neurochemistry International
Citation Excerpt :
Interaction of neurotrophin to Trk receptors promotes cell growth, survival or differentiation while binding of neurotrophin to p75NTR have been widely known to be involved in cell death mechanism mainly apoptosis (Bibel and Barde, 2000; Chao, 2003). The association between neurotrophin and p75NTR/Trk heterodimer interactions could result in either cell survival or cell death (Eide et al., 1993; Friedman and Green, 1999). Although NGF was first discovered in snake venoms (Cohen and Levi-Montalcini, 1956), the NGFs isolated from the mouse submaxillary glands (mouse NGF; Lipps, 1998) and human placental tissues and body fluids have been studied extensively (Goldstein et al., 1978 and Lipps, 2000).
Nerve growth factor (NGF) is synthesized as a precursor, proNGF that undergoes post-translational processing to generate the biologically active mature NGF. While the neurotrophic function of NGF is well established, the activity of the proNGF precursor is still unclear. In this study, we have cloned the pro-domain of the precursor NGF molecule and have elucidated its function. We have used both mature and the furin resistant pro^(R/G)NGF as controls in our experiments. Both pro^(R/G)NGF and mature NGF (NGF) exhibited neurotrophic activity on PC12 cells while the pro-domain itself promoted cell death. The pro-domain, has been found to mediate apoptosis possibly by promoting the formation of a signaling complex comprising of endogenous p75^NTR receptor, Bim/Bcl2 group of proteins and JNK and MEK1/2 signaling pathways.
Activation of dendritic-like cells and neural stem/progenitor cells in injured spinal cord by GM-CSF
2009, Neuroscience Research
Previously, we demonstrated that implanted dendritic cells (DCs) in the injured spinal cord of adult mice exert a neurotrophic effect, resulting in the activation of endogenous neural stem/progenitor cells (NSPCs) and neurogenesis. Granulocyte–macrophage colony stimulating factor (GM-CSF), which is an essential cytokine for the generation of DCs from haematopoietic progenitor cells, has been shown to be beneficial for the treatment of spinal cord injury (SCI). In the present study, to evaluate the mechanisms underlying this therapeutic efficacy of GM-CSF, we investigated the effects of GM-CSF on the DC-like cells and NSPCs in the injured spinal cord. When GM-CSF was injected into the injured spinal cords of mice, the numbers of DC-like cells and activated microglia/macrophages around the lesion site increased, accompanied by an increase in BDNF expression. A significant increase in endogenous NSPCs was observed around the lesion site in the GM-CSF-treated mice compared with that in the controls. A neurosphere forming assay revealed that GM-CSF also induced the proliferation of NSPCs in vitro. Moreover, injection of GM-CSF into the lesion immediately after the SCI resulted in early recovery of the locomotor function of the injured mice. In conclusion, GM-CSF activated DC-like cells and NSPCs in the injured spinal cord, which was probably involved in its beneficial effects in cases of spinal cord injury.
Achyranthes bidentata Blume extract promotes neuronal growth in cultured embryonic rat hippocampal neurons
2009, Progress in Natural Science
We have prepared an aqueous extract of Achyranthes bidentata Blume, a commonly prescribed Chinese medicinal herb, and reported, in previous studies, that A. bidentata extract benefits nerve growth and prevents neuron apoptosis. In this study, we investigated the actions of A. bidentata extract on survival and growth of primarily cultured rat hippocampal neurons. The morphological observation revealed that neurite growth from hippocampal neurons was significantly enhanced by A. bidentata extract with similar effects to those induced by nerve growth factor (NGF), and the greatest neurite growth appeared on treatment with A. bidentata extract at 1 μg/ml for 24 h. DNA microarray analysis indicated that there were 25 upregulated genes and 47 downregulated genes exhibiting significantly differential expression in hippocampal neurons treated with A. bidentata extract at 1 μg/ml for 6 h when compared to those in untreated hippocampal neurons. Real-time quantitative RT-PCR and Western blot analysis demonstrated that the expression of growth-associated protein-43 in hippocampal neurons was upregulated at both mRNA and protein levels after treatment with A. bidentata extract, and the optimal dosage of the extract was also 1 μg/ml. These data confirm that A. bidentata extract could promote in vitro hippocampal neuronal growth in a dose- and time-dependent manner.
TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand
2007, Journal of Biological Chemistry
Neurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brain-derived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA “hot spot” functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucine-rich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with trun-cated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots.
Neural Upregulation in Interstitial Cystitis
2007, Urology
Citation Excerpt :
These studies support neurologic changes to the micturition reflex pathway after cystitis. Changes to central synapses lead to enhanced pain sensation.80–82 The pontine micturition center (PMC) connects with axon collaterals to the paraventricular thalamic nucleus (limbic system).
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Regular ArticleNeurotrophins and Their Receptors—Current Concepts and Implications for Neurologic Disease

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Neurotrophins and Their Receptors—Current Concepts and Implications for Neurologic Disease