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

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 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.

The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception

“…The mutated residues W160C, R168C, and E172D cluster in the PR methyltansferase domain, for which an X-ray structure is available (PDB: 3EP0). Residues R168 and E172 are 26 Xenopus animal cap explants isolated from embryos injected with noggin mRNA, together with wild type or mutated human Prdm12 mRNAs as indicated and treated with retinoic acid (RA). Data are presented as the mean § SEM of 3 idependent experiments.…”

Galectin-1 as a Multifunctional Molecule in the Peripheral Nervous System After Injury

“…Both small peptidergic and non-peptidergic neurons are responsible for the transmission of nociception and thermoreception, and whether these two groups of neurons have distinct functions has been the subject of controversy (McMahon & Bennett, 2000;Ernsberger, 2009). Fig.…”

Alternative TrkA Splicing and Neuroblastoma

“…Within the peripheral nervous system TrkA regulates the formation, differentiation and survival of sympathetic neurones that originate from progenitors of neural crest origin (Bibel & Barde, 2000;Kaplan & Miller, 2000;Oppenheim, 1991;Ernsberger, 2009). TrkA is also critical for the development and function of the immune system (Vega et al, 2003;Fiore et al, 2009).…”