The neurotrophins

The neurotrophins are a group of neurotrophic factors which all belong to the same gene family. They include NGF, as well as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5) and neurotrophin-6 (NT-6). All are small, basic proteins sharing approximately 50% amino acid homology. They exist mainly as homodimers and promote signal transduction by binding to a member of the Trk family of tyrosine kinase receptors (Table 7.10). 

NGF is the prototypic neurotrophin. The mature NGF polypeptide contains 120 amino acids, exhibits a molecular mass of 26 kDa and a pi of approximately 10. It contains three intra-chain disulphide linkages, which are essential for activity. NGF is synthesized and released from target tissues of sympathetic neurons and cholinergic basal forebrain neurons. It is also synthesized by non-neuronal tissue, including salivary glands, the prostate and mast cells. It functions to 

The neuronal cytoskeleton provides the axon with mechanical support and is directly involved in the transport of materials from the cell body towards the synapse (anterograde transport) and in the opposite direction (retrograde transport). Axons are generally covered (insulated) with a myelin sheath, which is formed by oligodendrocytes (in the CNS) or Schwann cells (PNS). 

Neurotrophic factors play a central role in development and maintenance of neuronal cells. After release from the target cells, they bind specific receptors on the nerve termini, are internalized and carried up the axon to the perikaryon by retrograde transport. This process helps guide the direction of neurite growth (i.e. a chemoattractant activity) during neuronal development, and also serves to nourish the developing cell. Once established, the process of retrograde transport must continue if the cell is to survive and remain differentiated. 

The restricted neuronal specificity of NGF suggested the existence of additional neurotrophic factors capable of influencing non-NGF-sensitive neuronal populations. Research efforts in the early 1980s led to the discovery of BDNF, a 119 amino acid (13.5 kDa) basic protein. In contrast to NGF, BDNF is predominantly localized within the CNS. Predictably, most BDNF-responsive neurons are located in (or project into) the CNS. 

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Kaplan, D. R. and Miller, F. D., Signal transduction by the neurotrophin receptors, Curr. Opin. Cell. Biol., 9, 213-212, 1997. 

Berhow, M.T., Hiroi, N., Nestler, EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J. Neurosci. 16 4707, 1996. 

The neurotrophins (NGF, brain-derived neurotrophic factor (BDNF), NT-3, NT-4/5)... 

Neurotrophic factors constitute a group of cytokines that regulate the development, maintenance and survival of neurons, both in the central and peripheral nervous systems (Table 10.12). Although the first member of this family (NGF) was discovered more than 50 years ago, it is only in the last decade that the other members have been identified and characterized. The major subfamily of neurotrophic factors is the neurotrophins. 

The best characterized family of MAPKs in the brain are the extracellular signal-regulated protein kinases (ERKs) that are activated by the neurotrophins and related growth factors (Fig. 23-4) [14,15]. The MAPK kinases responsible... 

The neurotrophins comprise a family of highly related molecules that act to support the survival and phenotypic specificity of select subsets of neurons 474... 

The neurotrophins comprise a family of highly related molecules that act to support the survival and phenotypic specificity of select subsets of neurons. The neurotrophins (Table 27-2) are small highly basic proteins of approximately 13kDa that dimerize to form the biologically active species [5]. The neurotrophins have a highly conserved structure. This family includes five distinct members NGF,brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), neurotrophin 4/5 (NT4/5) and neurotrophin 6 (NT6). NT6 is found only in fish and will not be discussed further. 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

The specific actions of the individual neurotrophins have been the subject of intense interest (Table 27-2). It is now evident, through analysis of animals in which the individual neurotrophin genes or their receptors have been knocked out, that the family members have unique actions acting exclusively to support some neuronal subpopulations [11]. However, in some neuronal populations, the action of several of the neurotrophins overlap. For example, in the peripheral sensory ganglia, individual neurons are responsive to more than one neurotrophin. 

Neurotrophin 3 is the most abundantly distributed of the neurotrophins and appears to have a wider range of action than other members of this family, particularly in the CNS. It is expressed throughout the CNS. In the mature brain, NT3 is found at high levels in the cortex, hippocampus, thalamus and cerebellum. NT3 also acts on subpopulations of spinal motor neurons and on cochlear neurons. It exerts its actions principally through binding to another member of the Trk family, TrkC. 

Neurotrophin 4/5 is not as well characterized as other members of the neurotrophin family. Much of what is known is derived from analysis of NT4/5 and TrkB knockout mice. Elucidating the actions of NT4/5 is complicated by virtue of the fact that both NT4/5 and BDNF exert their effects via the TrkB receptor. It appears that NT4/5 functions largely overlap with those of other neurotrophin family members, particularly BDNF. NT4/5 knockout mice are essentially normal, in contrast to BDNF knockout mice, which do not live long. NT4/5 is likely to have unique actions on a subpopulation of neurons in the nodose and geniculate ganglia, which are not supported by BDNF. Like BDNF, NT4/5 acts on sensory neurons and retinal ganglion cells, supporting their survival. 

Neurotrophins influence neurotransmission and synaptic plasticity. The discovery that the neurotrophins have acute effects in the mature nervous system and can modulate synaptic efficiency has forced a substantial reevaluation of the role of these molecules in modulating the dynamic behavior of the nervous system [12]. 

Snider, W. D. Functions of the neurotrophins during nervous system development what the knockouts are teaching us. Cell 77 627-638,1994. 

Table 7.10. Biochemical characteristic of the neurotrophin family of neurotrophic factors. Except for NT-6, the molecular masses quoted are those of the homodimeric structure, which represents their biologically active forms. See text for further details...

The synthesis of oligonucleotide primers, based upon conserved sequences between the NGF and BDNF genes, allowed researchers to fish for additional members of the neurotrophin family by PCR analysis. In 1991 this led to the discovery of neurotrophin 3 (NT-3), which is expressed early in — and throughout — embryogenesis. It supports the development of various neuronal populations in culture, although its role in vivo is less well understood. 

Most neurotrophin-sensitive cells express two receptor types on their surface a high-affinity receptor, which appears to mediate most/all of the biological actions of the neurotrophins, and a low-affinity receptor. The high-affinity receptors are all members of a family of tyrosine kinases (the Trks). They are similar to the receptors of many other growth factors, but are expressed almost exclusively on neuronal tissue. 

Ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) represent the most recently discovered members of the neurotrophic factor family. These, however, display no homology to the neurotrophins previously discussed. 

Such an approach could be underpinned by the development of engineered proteins displaying multiple neurotrophic activities. Pan-neurotrophin-1, for example, is an engineered chimaeric neurotrophin, containing the active domains of NGF, BDNF and NT-3. This hybrid molecule can bind the neurotrophin receptors Trk A, B and C, as well as P75. 

Allergic asthma patients have higher blood levels of NGF. The influx of inflammatory cells in lungs is observed as the neurotrophin expression is augmented. Multiple targets may be affected by neurotrophins as they play a role in allergic inflammation, which include recruitment, maintenance and activation of mast cells and eosinophils and facilitation of TH2 response. Whether neurotrophins can alter TH1/TH2 balance in humans has not yet been established. 

Nassenstein C, Braun A, Erpenbeck A, Lommatzsch M, et al. 2003. The neurotrophins nerve growth factors, brain derived neurotrophic factor, neurotrophin 3 and neurotrophin 4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma. J Exp Med. 198 455-467. 

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