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Functions and Mechanisms of Retrograde Neurotrophin Signalling

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Functions and Mechanisms of Retrograde Neurotrophin Signalling REVIEWS FUNCTIONS AND MECHANISMS OF RETROGRADE NEUROTROPHIN SIGNALLING Larry S. Zweifel*, Rejji Kuruvilla‡ and David D. Ginty* Abstract | Neuronal connections are established and refined through a series of developmental programs that involve axon and dendrite specification, process growth, target innervation, cell death and synaptogenesis. Many of these developmental events are regulated by target- derived neurotrophins and their receptors, which signal retrogradely over long distances from distal-most axons to neuronal cell bodies. Recent work has established many of the cellular and molecular events that underlie retrograde signalling and the importance of these events for both development and maintenance of proper neural connectivity. PRONEUROTROPHINS The correct establishment of neuronal connections effectors and the activation of numerous signal trans- Uncleaved forms of the in the central and peripheral nervous systems during duction cascades that support growth and survival3. neurotrophins that bind with development is essential for the proper function of the Both mature neurotrophins and PRONEUROTROPHINS also NTR high affinity to p75 . nervous system. Such connections are generated through bind to a structurally distinct neurotrophin receptor, p75 a developmental program that involves axon and den- (p75NTR), which also mediates neuronal development drite specification, process growth, target innervation, through local and retrograde signalling4. cell death, synaptogenesis and synaptic refinement. Many Early observations that neurotrophins are retro- target-derived factors are crucial for this developmental gradely transported from the target towards the cell body program. Of these instructive cues, the neurotrophins have led to decades of inquiry regarding not only the are perhaps the best described. However, although there underlying mechanism of this developmental phenom- is considerable evidence for their roles in development, enon but also the physiological significance of retrograde the precise molecular mechanisms that underlie retro- growth factor signalling. In this review, we summarize grade neurotrophin signal transduction from the tip of the functions of retrograde neurotrophin signalling dur- the axon to the soma remain unresolved. ing development and analyse the mechanisms through *Department of The neurotrophins are a family of low-molecular- which this signalling occurs. Neuroscience, Howard Hughes Medical Institute, weight proteins that includes the prototypical neuro tro - The Johns Hopkins phin nerve growth factor (NGF) as well as brain-derived Functions of retrograde signalling University School of neurotrophic factor (BDNF) and neurotrophins 3 and Regulation of neuronal survival. The importance of Medicine, Baltimore, 4/5 (NT3 and NT4/5). Each neurotrophin binds with target fields for the survival of developing neurons Maryland 21205-2185, high affinity to receptor tyrosine kinases known as was first disseminated through a series of elegant and USA. ‡Department of Biology, The Johns Hopkins Trk receptors; NGF binds to TrkA, BDNF and NT4/5 classical experiments in the chick. Ablation of the University Zanvyl Krieger to TrkB, and NT3 to TrkC 1,2. NT3 also binds TrkA chick wing bud was found to result in hypoplasia and School of Arts and Sciences, and TrkB. As in other families of receptor tyrosine death of brachial spinal motor neurons. Conversely, Baltimore, Maryland kinases, ligand binding induces dimerization of Trk transplantation of supernumery wing buds results in 21218, USA. 5–7 Correspondence to D.D.G. receptors and their autophosphorylation at specific increased numbers of neurons . It is now known that e-mail: [email protected] tyrosine residues in the cytoplasmic domain. This, in the establishment of the proper complement of neurons doi:10.1038/nrn1727 turn, leads to the recruitment of various downstream for a given target field is governed by a developmental NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | AUGUST 2005 | 615 © 2005 Nature Publishing Group REVIEWS abDistal Cell Distal neurons follow a stereotyped temporal progression axons bodies axons of apoptotic signalling events, which include the trans location of BAX to mitochondria, the release of cytochrome c, activation of the APOPTOSOME and caspase- mediated cell death12–15. Retrograde neurotrophin sig- nalling impinges on these apoptotic pathways (FIG. 2a), c Cell Middle Distal bodies axons axons in part by regu lating transcriptional events, such as those mediated by the transcription factor cyclic AMP responsive element-binding protein (CREB)14,16–18. In addition, several signalling cascades, such as the phos- phatidylinositol 3-kinase (PI3K)–Akt (v-akt murine thymoma viral oncogene homologue, also known as Cell Distal bodies axons protein kinase B) and Ras–Raf–MEK (MAPK (mitogen Figure 1 | Compartmentalized neuronal cell culture system. This in vitro model system is activated protein kinase)/ERK (extracellular signal-reg- used to study the retrograde transport of neurotrophins and their receptors, as well as ulated kinase) kinase)–ERK pathways, mediate retro- downstream events in retrograde neurotrophin signalling. Compartmented cultures of grade neurotrophin-dependent survival19–21. However, sympathetic and sensory neurons are established by placing Teflon dividers onto a thin layer much remains to be learned about how pro-survival and of vacuum grease, which allows diffusion-limited compartmentalization of neuronal cell bodies pro-apoptotic pathways intersect in developing neu- and distal axons11,108. a | Schematic top view of three-compartment culture chamber rons. Which downstream targets of PI3K and MITOGEN (Campenot chamber). b | Side view of compartmentalized culture depicting cell body and distal axon compartments. c | Side view of three-compartment chamber system used to ACTIVATED PROTEIN KINASE SIGNALLING are essential for neu- study spatial requirements of tyrosine receptor kinase (Trk) activity, and downstream pathways rotrophin-dependent survival? Which transcriptional such as phosphatidylinositol 3-kinase (PI3K)–Akt (v-akt murine thymoma viral oncogene targets downstream of retrograde neurotrophin signals homologue, also known as protein kinase B) signalling. Unlike conventional three- contribute to survival? To address these questions, it compartment chambers, cells are plated in one of the two side compartments, which allows will be helpful to merge recent advances in our under- axonal projections to be divided into a middle axon compartment and a distal axon standing of apoptosis and mitochondrial physiology compartment. Development of the compartmentalized cell culture system has revolutionized with improved spatial and temporal resolution of neuro- the study of retrograde neurotrophin signalling. trophin signalling pathways in compartmentalized cultures. In vivo analysis of transcriptional targets of retro- grade neurotrophin signalling, using, for example, Ngf/ sequence in which neurons are overproduced and then Bax and Nt3/Bax double mutants, in which deletion of compete for target-derived survival factors8. The con- the pro-apoptotic B-cell leukaemia/lymphoma 2 (Bcl2) trol of this developmental process is best understood family member Bax prevents neuronal apoptosis in the for PNS neurons. Several target-derived trophic fac- absence of neurotrophins22–25, will also prove beneficial. BAX tors, typified by NGF and other neurotrophins, have These types of investigation promise a better under- Pro-apoptotic BCL2 family been identified and found to be expressed in many standing of how and where apoptotic machinery and member. BAX translocation peripheral and central neuronal targets9. Antigenic pro-survival signalling intersect to regulate retrograde from the cytosol to the mitochondria facilitates neutralization and genetic ablation of these secreted neuronal survival. cytochrome c release. factors and their cognate receptors, as well as intra- peritoneal injection and transgenic overexpression of Regulation of axonal growth. As developing axons APOPTOSOME neurotrophins, have revealed that these target-derived traverse long distances towards their final targets, they Heteromeric protein complex containing cytochrome c, signals are essential for the growth and survival of respond to growth and guidance cues that are derived 7,9 APAF-1 and procaspase-9. select populations of developing PNS neurons . from both intermediate and final target fields. In com- Triggers a cascade of caspase How do target-derived signals, such as the neuro- partmentalized sympathetic neuronal cultures, the direct activation and proteolysis. trophins, influence neuronal survival? Disruption of application of NGF to distal axons, but not to cell bodies, neuron–target interactions through axonal transection supports the extension of these axons. Importantly, if Ras, Rap Small GTPases that are involved has shown that axonal transport of neurotrophic fac- NGF is removed from the distal axons but left in the in growth, differentiation and tors, or their downstream effectors, is necessary for their medium bathing the cell bodies, the distal axons retract cellular signalling. They require function10. Further insight into the nature of retrograde and degenerate, but the neurons survive11. Therefore, the binding of GTP to enter into neurotrophin signalling has been gained through the neurotrophin signalling initiated at distal axons is both their active state. use of compartmentalized cell culture systems (FIG. 1), necessary and sufficient to support
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