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Neurotrophins
Neurotrophins BL Hempstead, Weill Cornell Medical College, New York, NY, USA r 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Anita Bhattacharyya, Clive Svendsen, volume 3, pp 621–623, r 2003, Elsevier Inc.
Introduction Neurotrophins consist of a family of four highly homologous growth factors that promote survival, differentiation, and function of neurons during the development of the central and peripheral nervous systems. In adults, neurotrophins also play important roles in modulating synaptic plasticity and in regulating the response of the nervous system to injury and disease.
History Nerve growth factor (NGF) was the first soluble growth factor to be identified. Seminal experiments by Levi-Montalcini and Hamburger in the 1940s identified NGF as a growth factor synthesized by target organs that was critical for the development of peripheral neurons that innervated the target tissue. Removal of the limb bud in the chick embryo led to the death of peripheral neurons innervating the limb, implicating the production of a growth factor synthesized in peripheral targets that provided trophic support. With Stanley Cohen, they characterized the target-derived neuronal survival factor as NGF. In addition to its role in survival, NGF also facilitates outgrowth of axons from developing neurons, a tropic function. In the 1980s, a factor with similar neurotrophic and neurotrophic actions on central and peripheral neurons was purified from pig brain and termed brain-derived neurotrophic factor (BDNF). The amino acid sequences of NGF and BDNF demonstrate significant homology, suggesting that the two neurotrophins were structurally related. On the basis of the homology between NGF and BDNF, two additional members of this family were molecularly cloned. These include neurotrophin-3 (NT-3) and NT-4/5. A fifth NT, NT-6, has been identified in fish. Like most growth factors, neurotrophins are initially synthesized as a precursor (proneurotrophin), which encodes a prodomain and a mature domain. Intracellular cleavage of proneurotrophins leads to the release of C-terminal mature neurotrophins, with neurotrophic activities. In contrast, the prodomain regulates intracellular trafficking and protein folding. However, more recent experimental evidence suggests that proneurotrophins, specifically proNGF and proBDNF, can be secreted from cells, and that proNGF can mediate apoptosis. These studies have expanded the repertoire of biological functions for the neurotrophins.
Function Development The classic ‘neurotrophic hypothesis’ provides a model in which developing peripheral neurons compete for limited
Encyclopedia of the Neurological Sciences, Volume 3
amounts of target-derived neurotrophin (NT). Neurons are born in excess and only those whose axons innervate target cells and transport neurotrophins retrogradely will survive, whereas those with insufficient access to neurotrophins will die by apoptosis. NGF, BDNF, and NT-3 all participate in regulating target innervation. Neurotrophins are also synthesized locally by glial cells and neurons themselves and can medicate survival, migration, and proliferative effects during development. Neurotrophins also regulate the elaboration of dendritic processes, local guidance of developing axons, and acute growth cone turning. In addition, neurotrophins influence the formation of ocular dominance columns in the developing cortex. Lastly, proNGF is utilized in the developing retinal to induce programmed cell death of supernumerary neurons. Together, the varied and even divergent functions of neurotrophins underscore their importance in the development of the nervous system.
Adulthood Neurotrophins are synthesized throughout adult life, confirming that their functions are not confined to developmental processes. However, mature neurons lose their dependence on neurotrophins for survival and instead utilize neurotrophins to maintain neuronal phenotype and modulate synaptic function. Hence, they play critical roles to fine tune the structure and function of the nervous system in response to acute and chronic stimuli. Neuronal production of neurotrophins, particularly BDNF, increases with cell depolarization, implicating this factor in regulating activity-dependent processes such as synaptic plasticity. Impairment in the activitydependent synthesis of BDNF in mice leads to significant deficits in synaptic function (transmission) and structure (connectivity) in response to stimulus-dependent neuronal activity. Following injury and disease, neuronal phenotypes in the adult nervous system can be compromised. Mature neurotrophins can protect neurons from toxic events, such as cell death induced by axotomy, glutamate excitotoxicity, or diseases such as Huntington’s disease, in which the transport of BDNF to striatal neurons is compromised. In response to injury, the expression of neurotrophins is upregulated in both the peripheral and central nervous systems. Local release of mature neurotrophins can promote axon regeneration and nerve repair in the peripheral nervous system, and the regrowth and reorganization of central neural connections. However, with some forms of injury, including axotomy of central neurons and seizures, proNGF is rapidly induced and secreted, leading to neuronal apoptosis. The mechanisms that regulate whether the actions of proneurotrophins or mature neurotrophins predominate remain to be determined.
doi:10.1016/B978-0-12-385157-4.00069-5
583
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Neurotrophins
With aging, neurons become more susceptible to cell death. This may result from a deficiency of mature NT signaling, to induce cell atrophy and render the aging neurons more vulnerable to insult and injury. In addition, expression of proneurotrophins is increased in the aging central and peripheral nervous system, and in Alzheimer’s disease, and may promote neuronal dysfunction.
Structure and Signaling Factors, Receptors, and Pathways The mature neurotrophins are small polypeptides (12–13 kDa) that function as noncovalently associated homodimers released following cleavage from the initially translated 28–30 kDA proneurotrophins. The crystal structure of NGF reveals a tertiary fold and a cysteine knot. Neurotrophins are found in all mammals and lower vertebrates, and structurally-related proteins have been identified in invertebrates. Despite the high homology of neurotrophins, single-nucleotide polymorphisms (SNPs) in NT genes have been identified in human populations. Although the function of many of these SNPs is not known, one common polymorphism in BDNF, which encodes a valine to methionine substitution in the prodomain, leads to reduced BDNF release from neurons, and impairment in specific forms of learning, as well as susceptibility to anxiety disorders and depression. Neurotrophins mediate their effects by signaling through specific cell surface receptors – the tropomyosin-related kinase (Trk) and p75 receptors. Trk receptors exhibit selectivity, with TrkA binding NGF, TrkB binding BDNF and NT-4/5, and TrkC binding NT-3. Trk receptors are transmembrane proteins that encode tyrosine kinase activity and binding of the NT initiates intracellular signal transduction cascades, which include the mitogen-activated protein kinase pathways, the phosphoinositol-3-kinase pathway, and the phospholipase C-g pathway. Activation of specific pathways leads to the activation of specific genes that regulate how neurons respond to neurotrophins. In addition, Trk activation can lead to local signaling events in neurons, to modulate synaptic plasticity and acute remodeling of dendritic structures. The transmembrane receptor p75 is a member of the tumor necrosis factor receptor family, and encodes an intracellular death domain. P75 binds to all mature neurotrophins, and can modulate Trk signaling via direct actions and through effects on signal transduction. In addition, p75 acts together with the transmembrane receptor sortilin to bind to proNGF and initiate cell death. Numerous signaling cascades can be initiated by p75, although apoptotic signaling is induced by the activation of phospho-C-jun N-terminal kinase (JNK) and caspase-3. Collectively, these results suggest that the response of neurons to neurotrophins is regulated both by the form of NT (proneurotrophin or mature NT) and by the receptor complex on the cell surface.
Signaling Location The biological actions of neurotrophins also differ depending on the location at which a neuron is stimulated. In general,
peripheral neurons can be stimulated at their axons (target derived), or locally at their cell bodies. Target-derived neurotrophins bind to receptors on the axon and the NT/receptor complex is endocytosed into signaling endosomes. These are transported retrogradely to the cell body and culminate in changes in gene expression. In addition to stimulating retrograde transcriptional responses, NT signaling can also occur locally at axonal endings to initiate neuronal outgrowth. Local delivery of neurotrophins at the cell bodies of neurons can also promote survival. Specifically, distinct mitogen activated protein-kinase species are activated by Trks at the cell body as compared with those activated by retrograde Trk signaling. This allows a cell to interpret where NT signaling is originating. In the central nervous system, neurotrophins, particularly BDNF, can modulate synaptic activity. Neurotrophins can be anterogradely transported to axons and released from a neuron following depolarization. Trk receptors are present on the dendritic spines of postsynaptic neurons, and activation leads to an enhanced synaptic activity. Impairment in the central action of BDNF contributes to numerous behavioral effects, including susceptibility to depression, aggression, abnormal feeding behavior, and abnormalities in learning and memory.
Conclusion NT research started with a single factor (NGF) with survivalpromoting effects on specific developing neurons and has blossomed into a field involving numerous neurotrophins and their isoforms, and multiple NT receptors with diverse functions in the developing, mature, and the injured nervous system. Although much progress has been made with regard to the functions of neurotrophins, research has underscored the immense complexity of the NT field. Many important aspects of NT function are likely to be uncovered in the future.
See also: Neurotrophic Signals, Axonal Transport of. Vertebrate Nervous System, Development of the
Further Reading Ascano M, Bodmer D, and Kuruvilla R (2012) Endocytic trafficking of neurotrophines in neural development. Trends in Cell Biology 22: 266–273. Hamburger V and Levi-Montalcini R (1949) Proliferation, differentiation and degeneration in the spinal ganglia of the chick embryo under normal and experimental conditions. Journal of Experimental Zoology 111: 457–502. Hohn A, Leibrock J, Bailey K, and Barde YA (1990) Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344: 339–341. Huang EJ and Reichardt LF (2001) Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience 24: 677–736. Martinowich K, Manji H, and Lu B (2007) New insights into BDNF function in depression and anxiety. Neuroscience 10: 1089–1093. Patapoutian A and Reichardt LF (2001) Trk receptors: Mediators of neurotrophin action. Current Opinion in Neurobiology 11: 272–280. Teng KK, Felice S, Kim T, and Hempstead BL (2010) Understanding proneurotrophin actions: Recent advances and challenges. Developmental Neurobiology 70: 350–359. Wu C, Cui B, He L, Chen L, and Mobley WC (2009) The coming of age of axonal neurotrophin signaling endosomes. Journal of Proteomics 72: 46–55.
Introduction Neurotrophins consist of a family of four highly homologous growth factors that promote survival, differentiation, and function of neurons during the development of the central and peripheral nervous systems. In adults, neurotrophins also play important roles in modulating synaptic plasticity and in regulating the response of the nervous system to injury and disease.
History Nerve growth factor (NGF) was the first soluble growth factor to be identified. Seminal experiments by Levi-Montalcini and Hamburger in the 1940s identified NGF as a growth factor synthesized by target organs that was critical for the development of peripheral neurons that innervated the target tissue. Removal of the limb bud in the chick embryo led to the death of peripheral neurons innervating the limb, implicating the production of a growth factor synthesized in peripheral targets that provided trophic support. With Stanley Cohen, they characterized the target-derived neuronal survival factor as NGF. In addition to its role in survival, NGF also facilitates outgrowth of axons from developing neurons, a tropic function. In the 1980s, a factor with similar neurotrophic and neurotrophic actions on central and peripheral neurons was purified from pig brain and termed brain-derived neurotrophic factor (BDNF). The amino acid sequences of NGF and BDNF demonstrate significant homology, suggesting that the two neurotrophins were structurally related. On the basis of the homology between NGF and BDNF, two additional members of this family were molecularly cloned. These include neurotrophin-3 (NT-3) and NT-4/5. A fifth NT, NT-6, has been identified in fish. Like most growth factors, neurotrophins are initially synthesized as a precursor (proneurotrophin), which encodes a prodomain and a mature domain. Intracellular cleavage of proneurotrophins leads to the release of C-terminal mature neurotrophins, with neurotrophic activities. In contrast, the prodomain regulates intracellular trafficking and protein folding. However, more recent experimental evidence suggests that proneurotrophins, specifically proNGF and proBDNF, can be secreted from cells, and that proNGF can mediate apoptosis. These studies have expanded the repertoire of biological functions for the neurotrophins.
Function Development The classic ‘neurotrophic hypothesis’ provides a model in which developing peripheral neurons compete for limited
Encyclopedia of the Neurological Sciences, Volume 3
amounts of target-derived neurotrophin (NT). Neurons are born in excess and only those whose axons innervate target cells and transport neurotrophins retrogradely will survive, whereas those with insufficient access to neurotrophins will die by apoptosis. NGF, BDNF, and NT-3 all participate in regulating target innervation. Neurotrophins are also synthesized locally by glial cells and neurons themselves and can medicate survival, migration, and proliferative effects during development. Neurotrophins also regulate the elaboration of dendritic processes, local guidance of developing axons, and acute growth cone turning. In addition, neurotrophins influence the formation of ocular dominance columns in the developing cortex. Lastly, proNGF is utilized in the developing retinal to induce programmed cell death of supernumerary neurons. Together, the varied and even divergent functions of neurotrophins underscore their importance in the development of the nervous system.
Adulthood Neurotrophins are synthesized throughout adult life, confirming that their functions are not confined to developmental processes. However, mature neurons lose their dependence on neurotrophins for survival and instead utilize neurotrophins to maintain neuronal phenotype and modulate synaptic function. Hence, they play critical roles to fine tune the structure and function of the nervous system in response to acute and chronic stimuli. Neuronal production of neurotrophins, particularly BDNF, increases with cell depolarization, implicating this factor in regulating activity-dependent processes such as synaptic plasticity. Impairment in the activitydependent synthesis of BDNF in mice leads to significant deficits in synaptic function (transmission) and structure (connectivity) in response to stimulus-dependent neuronal activity. Following injury and disease, neuronal phenotypes in the adult nervous system can be compromised. Mature neurotrophins can protect neurons from toxic events, such as cell death induced by axotomy, glutamate excitotoxicity, or diseases such as Huntington’s disease, in which the transport of BDNF to striatal neurons is compromised. In response to injury, the expression of neurotrophins is upregulated in both the peripheral and central nervous systems. Local release of mature neurotrophins can promote axon regeneration and nerve repair in the peripheral nervous system, and the regrowth and reorganization of central neural connections. However, with some forms of injury, including axotomy of central neurons and seizures, proNGF is rapidly induced and secreted, leading to neuronal apoptosis. The mechanisms that regulate whether the actions of proneurotrophins or mature neurotrophins predominate remain to be determined.
doi:10.1016/B978-0-12-385157-4.00069-5
583
584
Neurotrophins
With aging, neurons become more susceptible to cell death. This may result from a deficiency of mature NT signaling, to induce cell atrophy and render the aging neurons more vulnerable to insult and injury. In addition, expression of proneurotrophins is increased in the aging central and peripheral nervous system, and in Alzheimer’s disease, and may promote neuronal dysfunction.
Structure and Signaling Factors, Receptors, and Pathways The mature neurotrophins are small polypeptides (12–13 kDa) that function as noncovalently associated homodimers released following cleavage from the initially translated 28–30 kDA proneurotrophins. The crystal structure of NGF reveals a tertiary fold and a cysteine knot. Neurotrophins are found in all mammals and lower vertebrates, and structurally-related proteins have been identified in invertebrates. Despite the high homology of neurotrophins, single-nucleotide polymorphisms (SNPs) in NT genes have been identified in human populations. Although the function of many of these SNPs is not known, one common polymorphism in BDNF, which encodes a valine to methionine substitution in the prodomain, leads to reduced BDNF release from neurons, and impairment in specific forms of learning, as well as susceptibility to anxiety disorders and depression. Neurotrophins mediate their effects by signaling through specific cell surface receptors – the tropomyosin-related kinase (Trk) and p75 receptors. Trk receptors exhibit selectivity, with TrkA binding NGF, TrkB binding BDNF and NT-4/5, and TrkC binding NT-3. Trk receptors are transmembrane proteins that encode tyrosine kinase activity and binding of the NT initiates intracellular signal transduction cascades, which include the mitogen-activated protein kinase pathways, the phosphoinositol-3-kinase pathway, and the phospholipase C-g pathway. Activation of specific pathways leads to the activation of specific genes that regulate how neurons respond to neurotrophins. In addition, Trk activation can lead to local signaling events in neurons, to modulate synaptic plasticity and acute remodeling of dendritic structures. The transmembrane receptor p75 is a member of the tumor necrosis factor receptor family, and encodes an intracellular death domain. P75 binds to all mature neurotrophins, and can modulate Trk signaling via direct actions and through effects on signal transduction. In addition, p75 acts together with the transmembrane receptor sortilin to bind to proNGF and initiate cell death. Numerous signaling cascades can be initiated by p75, although apoptotic signaling is induced by the activation of phospho-C-jun N-terminal kinase (JNK) and caspase-3. Collectively, these results suggest that the response of neurons to neurotrophins is regulated both by the form of NT (proneurotrophin or mature NT) and by the receptor complex on the cell surface.
Signaling Location The biological actions of neurotrophins also differ depending on the location at which a neuron is stimulated. In general,
peripheral neurons can be stimulated at their axons (target derived), or locally at their cell bodies. Target-derived neurotrophins bind to receptors on the axon and the NT/receptor complex is endocytosed into signaling endosomes. These are transported retrogradely to the cell body and culminate in changes in gene expression. In addition to stimulating retrograde transcriptional responses, NT signaling can also occur locally at axonal endings to initiate neuronal outgrowth. Local delivery of neurotrophins at the cell bodies of neurons can also promote survival. Specifically, distinct mitogen activated protein-kinase species are activated by Trks at the cell body as compared with those activated by retrograde Trk signaling. This allows a cell to interpret where NT signaling is originating. In the central nervous system, neurotrophins, particularly BDNF, can modulate synaptic activity. Neurotrophins can be anterogradely transported to axons and released from a neuron following depolarization. Trk receptors are present on the dendritic spines of postsynaptic neurons, and activation leads to an enhanced synaptic activity. Impairment in the central action of BDNF contributes to numerous behavioral effects, including susceptibility to depression, aggression, abnormal feeding behavior, and abnormalities in learning and memory.
Conclusion NT research started with a single factor (NGF) with survivalpromoting effects on specific developing neurons and has blossomed into a field involving numerous neurotrophins and their isoforms, and multiple NT receptors with diverse functions in the developing, mature, and the injured nervous system. Although much progress has been made with regard to the functions of neurotrophins, research has underscored the immense complexity of the NT field. Many important aspects of NT function are likely to be uncovered in the future.
See also: Neurotrophic Signals, Axonal Transport of. Vertebrate Nervous System, Development of the
Further Reading Ascano M, Bodmer D, and Kuruvilla R (2012) Endocytic trafficking of neurotrophines in neural development. Trends in Cell Biology 22: 266–273. Hamburger V and Levi-Montalcini R (1949) Proliferation, differentiation and degeneration in the spinal ganglia of the chick embryo under normal and experimental conditions. Journal of Experimental Zoology 111: 457–502. Hohn A, Leibrock J, Bailey K, and Barde YA (1990) Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344: 339–341. Huang EJ and Reichardt LF (2001) Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience 24: 677–736. Martinowich K, Manji H, and Lu B (2007) New insights into BDNF function in depression and anxiety. Neuroscience 10: 1089–1093. Patapoutian A and Reichardt LF (2001) Trk receptors: Mediators of neurotrophin action. Current Opinion in Neurobiology 11: 272–280. Teng KK, Felice S, Kim T, and Hempstead BL (2010) Understanding proneurotrophin actions: Recent advances and challenges. Developmental Neurobiology 70: 350–359. Wu C, Cui B, He L, Chen L, and Mobley WC (2009) The coming of age of axonal neurotrophin signaling endosomes. Journal of Proteomics 72: 46–55.