Neurotrophin-4: a survival factor for adult sensory neurons.

Growth Factor and Regeneration Group, Max Delbrück Institute for Molecular Medicine, D-13122, Berlin-Buch, Germany.
Current Biology (Impact Factor: 9.57). 09/2002; 12(16):1401-4.
Source: PubMed

ABSTRACT The nerve growth factor (NGF) family of neurotrophins provides a substantial part of the normal trophic support for sensory neurons during development. Although these neurotrophins, which include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4), continue to be expressed into adulthood, there is little evidence that they are survival factors for adult neurons. Here we have examined the age-dependent neurotrophic requirements of a specialized type of mechanoreceptive neuron, called a D-hair receptor, in the dorsal root ganglion (DRG). Studies using knockout mice have demonstrated that the survival of D-hair receptors is dependent upon both NT-3 and NT-4. Here, we show that the time period when D-hair receptors require these two neurotrophins is different. Survival of D-hair receptors depends on NT-3 early in postnatal development and NT-4 later in the mature animal. The age-dependent loss of D-hair neurons in older NT-4 knockout mice was accompanied by a large reduction (78%) in neurons positive for the NT-4 receptor (trkB) together with neuronal apoptosis in the DRG. This is the first evidence that sensory neurons have a physiological requirement for a single neurotrophin for their continued survival in the adult.

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Available from: Cheryl Stucky, Mar 11, 2014
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    • "However, their firing properties in the adult are determined by BDNF-TrkB signalling (Carroll et al. 1998). TrkB-NT4 signalling is necessary for the survival of adult D-hair mechanoreceptors (Stucky et al. 2002), but 40 % of these afferents are also lost during early development in NT3-deficient mice. The above examples demonstrate that different aspects of sensory neuron development (survival, axon growth, physiological functions) can be under the influence of different neurotrophins-Trk receptor signalling at different times during their development. "
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    ABSTRACT: Somatosensory neurons of the dorsal root ganglia are generated from multipotent neural crest cells by a process of progressive specification and differentiation. Intrinsic transcription programmes active in somatosensory neuron progenitors and early post-mitotic neurons drive the cell-type expression of neurotrophin receptors. In turn, signalling by members of the neurotrophin family controls expression of transcription factors that regulate neuronal sub-type specification. This chapter explores the mechanisms by which this crosstalk between neurotrophin signalling and transcription programmes generates the diverse functional sub-types of somatosensory neurons found in the mature animal.
    Handbook of experimental pharmacology 03/2014; 220:329-53. DOI:10.1007/978-3-642-45106-5_13
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    • "The effect of the NT4 mutation on D hair receptors becomes apparent around the 7th postnatal week (Stucky et al. 2002a). Whereas myelinated axons are reduced as early as 5 weeks after birth, D hair receptor number appears unchanged at this "
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    ABSTRACT: Manipulation of neurotrophin (NT) signalling by administration or depletion of NTs, by transgenic overexpression or by deletion of genes coding for NTs and their receptors has demonstrated the importance of NT signalling for the survival and differentiation of neurons in sympathetic and dorsal root ganglia (DRG). Combination with mutation of the proapoptotic Bax gene allows the separation of survival and differentiation effects. These studies together with cell culture analysis suggest that NT signalling directly regulates the differentiation of neuron subpopulations and their integration into neural networks. The high-affinity NT receptors trkA, trkB and trkC are restricted to subpopulations of mature neurons, whereas their expression at early developmental stages largely overlaps. trkC is expressed throughout sympathetic ganglia and DRG early after ganglion formation but becomes restricted to small neuron subpopulations during embryogenesis when trkA is turned on. The temporal relationship between trkA and trkC expression is conserved between sympathetic ganglia and DRG. In DRG, NGF signalling is required not only for survival, but also for the differentiation of nociceptors. Expression of neuropeptides calcitonin gene-related peptide and substance P, which specify peptidergic nociceptors, depends on nerve growth factor (NGF) signalling. ret expression indicative of non-peptidergic nociceptors is also promoted by the NGF-signalling pathway. Regulation of TRP channels by NGF signalling might specify the temperature sensitivity of afferent neurons embryonically. The manipulation of NGF levels "tunes" heat sensitivity in nociceptors at postnatal and adult stages. Brain-derived neurotrophic factor signalling is required for subpopulations of DRG neurons that are not fully characterized; it affects mechanical sensitivity in slowly adapting, low-threshold mechanoreceptors and might involve the regulation of DEG/ENaC ion channels. NT3 signalling is required for the generation and survival of various DRG neuron classes, in particular proprioceptors. Its importance for peripheral projections and central connectivity of proprioceptors demonstrates the significance of NT signalling for integrating responsive neurons in neural networks. The molecular targets of NT3 signalling in proprioceptor differentiation remain to be characterized. In sympathetic ganglia, NGF signalling regulates dendritic development and axonal projections. Its role in the specification of other neuronal properties is less well analysed. In vitro analysis suggests the involvement of NT signalling in the choice between the noradrenergic and cholinergic transmitter phenotype, in the expression of various classes of ion channels and for target connectivity. In vivo analysis is required to show the degree to which NT signalling regulates these sympathetic neuron properties in developing embryos and postnatally.
    Cell and Tissue Research 05/2009; 336(3):349-84. DOI:10.1007/s00441-009-0784-z · 3.57 Impact Factor
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    • "Although NGF supports the small diameter sensory neurons predominantly involved in thermal nociception, these neurons represent ∼25% of the total DRG population. The remaining populations, similarly vulnerable to diabetic insult, are supported by NT-3, neurotrophin-4, and GDNF, among other growth factors (Priestley et al., 2002; Stucky et al., 2002), and these neurons likely also play a role in responses to thermal stimuli (Stucky and Lewin, 1999). Furthermore, measurement of thermal nociception requires measurement of a motor response, and it is possible that compromised motor function may be a significant component of the longer response times in the Hargreaves test measured at terminal stages of the disease. "
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    ABSTRACT: A previous phase III clinical trial failed to show significant therapeutic benefit of repeated subcutaneous nerve growth factor (NGF) administration in the treatment of diabetic neuropathy. Animal studies have since shown that site-specific viral-mediated expression of NGF in the lumbar dorsal root ganglia prevents peripheral nerve dysfunction associated with chemically induced neuropathy. Using a Herpes simplex virus expression vector, we have investigated the effect of localized NGF expression in a genetic mouse model of progressive diabetic neuropathy, the +/+ Leprdb mouse. We found that site-specific delivery of NGF initially delayed the appearance of hypoalgesia, assessed by the Hargreaves test, by 1 month and effectively attenuated this deficit for 2 months over the approximately 10 months normal life-span of these animals. Once the disease progressed into its more severe stages, NGF, although still capable of altering the electrophysiological profile of the sensory A- and C-fibers and influencing the expression of p75 and substance P in the dorsal root ganglia, could no longer maintain normal nociception. These data suggest that maximal therapeutic benefit in future NGF-based gene therapy trials will be gained from early applications of such viral-mediated neurotrophin delivery.
    Experimental Neurology 04/2006; 198(1):260-70. DOI:10.1016/j.expneurol.2005.12.006 · 4.70 Impact Factor
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