Synchronous Onset of NGF and TrkA Survival Dependence in Developing Dorsal Root Ganglia

White, Fletcher A.; Silos‐Santiago, Inmaculada; Molliver, Derek C.; Nishimura, Merry; Phillips, Heidi S.; Barbacid, Mariano; Snider, William D.

doi:10.1523/jneurosci.16-15-04662.1996

Cited by 148 publications

(171 citation statements)

References 51 publications

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“…There are several possible explanations for this finding. It is known that DRG neurons can switch neurotrophin dependency during development [32], and that in some situations NT-3 can act through the non-selective low-affinity (p75) neurotrophin receptor to achieve protective effect [33]. We found in our experiments that NT-3 produced from the vector results in phosphorylation of the TrkA high-affinity NGF receptor in primary DRG neurons in culture.…”

Section: Discussionmentioning

confidence: 60%

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

Chattopadhyay¹,

Mata²,

Goss³

et al. 2007

Diabetologia

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Aims/hypothesis The aim of this study was to determine whether prolonged expression of neurotrophin-3 (NT-3) in mice, achieved by herpes simplex virus (HSV)-mediated gene transfer with gene expression under the control of an HSV latency promoter, can provide protection against the progression of diabetic neuropathy over a 6 month period. Materials and methods Mice with diabetes induced by streptozotocin were inoculated s.c. into both hind feet with a non-replicating HSV vector containing the coding sequence for NT-3 under the control of the HSV latencyassociated promoter 2 (LAP2) elements or with a control vector. Nerve function was evaluated by electrophysiological and behavioural measures over the course of 6 months after the onset of diabetes. Results Animals inoculated with the NT-3-expressing vector, but not animals inoculated with control vector, showed preservation of sensory and motor nerve amplitude and conduction velocity measured electrophysiologically, small fibre sensory function assessed by withdrawal from heat, autonomic function measured by pilocarpine-induced sweating, skin innervation assessed by protein gene product 9.5 staining of axons, and density of calcitonin gene-related peptide terminals in the spinal cord measured by immunohistochemistry 5.5 months after vector inoculation. Conclusions/interpretation These results indicate that the continuous production of NT-3 by LAP2-driven expression of the transgene from an HSV vector over a 6 month period protects against progression of diabetic neuropathy in mice, and provide a proof-of-principle demonstration for the development of a novel therapy for preventing the progression of diabetic neuropathy.

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Section: Discussionmentioning

confidence: 60%

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

Chattopadhyay¹,

Mata²,

Goss³

et al. 2007

Diabetologia

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“…2, Tables 2 (IHC) indicate an onset of expression in cervical and lumbar DRG of mouse embryos at E10.5 when expression levels are low and only a few positive cells are detectable (Phillips and Armanini 1996;White et al 1996). A rapid increase in the number of trkA-positive cells occurs thereafter.…”

Section: Developmental Expression Of Genes Specifying Neuronal Diversitymentioning

confidence: 98%

“…As early as E11,~20% of L1 DRG neurons express trkA immunoreactivity and their number increases dramatically over the next two days (Farinas et al 1998). trkA-immunoreactive cells do not incorporate BrdU, have neuronal bipolar morphology and are immunoreactive for the neurofilament 150-kDa subunit indicating that neurons, but not precursors, express the high-affinity NGF receptor (Farinas et al 1998;White et al 1996). Moreover, in chick embryos, no dividing cells are trkA-immunoreactive (Rifkin et al 2000).…”

Section: Developmental Expression Of Genes Specifying Neuronal Diversitymentioning

confidence: 99%

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

2009

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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 nonpeptidergic nociceptors is also promoted by the NGFsignalling 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.

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“…Programmed cell death of DRG neurons caused by competition for limited amounts of target-derived survival factors occurs between E11 and E17 in the mouse (Farinas et al 1996;White et al 1996). To determine whether HGF, in addition to its effects on axonal growth, also has neurotrophic activity, DRG neurons were isolated from E12 mouse embryos, dissociated and cultured in defined medium without added factors, with HGF, neurotrophins, or with combinations of factors.…”

Section: Hgf Enhances the Survival Of Cultured Drg Neurons Supported mentioning

confidence: 99%

Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons

Maina¹,

Hilton²,

Ponzetto³

et al. 1997

Genes Dev.

216

168

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The development of the nervous system is a dynamic process during which factors act in an instructive fashion to direct the differentiation and survival of neurons, and to induce axonal outgrowth, guidance to, and terminal branching within the target tissue. Here we report that mice expressing signaling mutants of the hepatocyte growth factor (HGF) receptor, the Met tyrosine kinase, show a striking reduction of sensory nerves innervating the skin of the limbs and thorax, implicating the HGF/Met system in sensory neuron development. Using in vitro assays, we find that HGF cooperates with nerve growth factor (NGF) to enhance axonal outgrowth from cultured dorsal root ganglion (DRG) neurons. HGF also enhances the neurotrophic activities of NGF in vitro, and Met receptor signaling is required for the survival of a proportion of DRG neurons in vivo. This synergism is specific for NGF but not for the related neurotrophins BDNF and NT3. By using a mild signaling mutant of Met, we have demonstrated previously that Met requires signaling via the adapter molecule Grb2 to induce proliferation of myoblasts. In contrast, the actions of HGF on sensory neurons are mediated by Met effectors distinct from Grb2. Our findings demonstrate a requirement for Met signaling in neurons during development.

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Synchronous Onset of NGF and TrkA Survival Dependence in Developing Dorsal Root Ganglia

Cited by 148 publications

References 51 publications

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons

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