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Neurotrophic factor receptor expression and in vitro nerve growth of geniculate ganglion neurons that supply divergent nerves.

ABSTRACT: We investigated which neurotrophic factors may contribute to the divergence of two peripheral nerves emanating from the geniculate ganglion. We compared receptor mRNA profiles of the neurons that supply the nerves, and also the growth of their neurites in response to neurotrophic factors in culture. Three mRNAs, Gfra2, TrkA, and TrkC, were differentially expressed. Only one ligand, Neurturin, promoted substantially different nerve regrowth from the nerves, and therefore may contribute to nerve divergence. Three receptor mRNAs were expressed in 100% of the neurons: TrkB, TrkB.T2 (kinase-lacking isoform), and NCAM-140. Ligands for these Trks and FRalpha-1 promoted more outgrowth than ligands for the other receptors. NT-3 and BDNF synergistically promoted outgrowth. Finally, receptors are coexpressed at random rates, arguing against the existence of neuronal subtypes defined by a combinatorial code of these receptors.

SUBMITTER: Yamout A

PROVIDER: S-EPMC4764251 | biostudies-literature | 2005 Sep-Oct

REPOSITORIES: biostudies-literature

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Neurotrophic factor receptor expression and in vitro nerve growth of geniculate ganglion neurons that supply divergent nerves.

Yamout Adam A Spec Andrej A Cosmano Jason J Kashyap Manoj M Kashyap Manoj M Rochlin M William MW

Developmental neuroscience 20050901 5

We investigated which neurotrophic factors may contribute to the divergence of two peripheral nerves emanating from the geniculate ganglion. We compared receptor mRNA profiles of the neurons that supply the nerves, and also the growth of their neurites in response to neurotrophic factors in culture. Three mRNAs, Gfra2, TrkA, and TrkC, were differentially expressed. Only one ligand, Neurturin, promoted substantially different nerve regrowth from the nerves, and therefore may contribute to nerve d ...[more]

PMID: 16137986

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Project description:Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two major members of the neurotrophin family. Using immunohistochemistry and in situ hybridization histochemistry, we examined the effect of L5 spinal nerve ligation (SPNL), a neuropathic pain model, on the expression of BDNF in the uninjured L4 dorsal root ganglion (DRG). After L5 SPNL, both immunoreactivity for BDNF and the hybridization intensity for BDNF mRNA increased mainly in the small- and medium-sized neurons. The percentage of BDNF mRNA-expressing neurons increased in the ipsilateral L4 DRG compared with the contralateral DRG from the third to 28th day after ligation. A significantly greater number of BDNF-immunoreactive neurons were observed in the ipsilateral L4 DRG than contralateral side 14 d after ligation. To test the contribution of BDNF to the thermal hyperalgesia produced in this model, we intrathecally injected anti-BDNF antibody at third day after ligation. This treatment clearly attenuated thermal hyperalgesia for a few hours. Almost all BDNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor, mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significantly increased in the ipsilateral L4 DRG 14 d after ligation. Furthermore, we examined the contribution of NGF on this phenotypic change using ELISA, Northern blot analysis, and anti-NGF antibody. NGF content in the ipsilateral L4 DRG linearly increased and reached a statistical significant level 14 d after L5 SPNL. Moreover, at this time point, the increase in NGF mRNA was observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsilateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody to the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented the development of thermal hyperalgesia for 5 d after ligation. Our data suggest that BDNF, which increased in the uninjured L4 DRG neurons, acts as a sensory neuromodulator in the dorsal horn and contributes to thermal hyperalgesia in this neuropathic pain model. The contribution of locally synthesized NGF to thermal hyperalgesia was also demonstrated. These dynamic alterations in the expression and content of BDNF and NGF in the uninjured DRG neurons might be involved in the pathomechanisms of neuropathic pain.

Project description:Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1? and tumor necrosis factor-? (TNF?) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNF? on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-h treatment with TNF? increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNF? increases the phosphorylated form of the cyclic AMP-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNF?-mediated increase in BDNF expression is accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNF? on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNF?-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNF? stimulates de novo synthesis of BDNF in these neurons. Thus, TNF? should be considered in mechanisms of BDNF-dependent neuronal plasticity.

Dataset Information

Neurotrophic factor receptor expression and in vitro nerve growth of geniculate ganglion neurons that supply divergent nerves.

Publications

Neurotrophic factor receptor expression and in vitro nerve growth of geniculate ganglion neurons that supply divergent nerves.

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