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Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury

Wang, T and Molliver, DC and Jing, X and Schwartz, ES and Yang, FC and Samad, OA and Ma, Q and Davis, BM (2011) Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury. PLoS ONE, 6 (12).

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In adult mammals, the phenotype of half of all pain-sensing (nociceptive) sensory neurons is tonically modulated by growth factors in the glial cell line-derived neurotrophic factor (GDNF) family that includes GDNF, artemin (ARTN) and neurturin (NRTN). Each family member binds a distinct GFRα family co-receptor, such that GDNF, NRTN and ARTN bind GFRα1, -α2, and -α3, respectively. Previous studies revealed transcriptional regulation of all three receptors in following axotomy, possibly in response to changes in growth factor availability. Here, we examined changes in the expression of GFRα1-3 in response to injury in vivo and in vitro. We found that after dissociation of adult sensory ganglia, up to 27% of neurons die within 4 days (d) in culture and this can be prevented by nerve growth factor (NGF), GDNF and ARTN, but not NRTN. Moreover, up-regulation of ATF3 (a marker of neuronal injury) in vitro could be prevented by NGF and ARTN, but not by GDNF or NRTN. The lack of NRTN efficacy was correlated with rapid and near-complete loss of GFRα2 immunoreactivity. By retrogradely-labeling cutaneous afferents in vivo prior to nerve cut, we demonstrated that GFRα2-positive neurons switch phenotype following injury and begin to express GFRα3 as well as the capsaicin receptor, transient receptor potential vanilloid 1(TRPV1), an important transducer of noxious stimuli. This switch was correlated with down-regulation of Runt-related transcription factor 1 (Runx1), a transcription factor that controls expression of GFRα2 and TRPV1 during development. These studies show that NRTN-responsive neurons are unique with respect to their plasticity and response to injury, and suggest that Runx1 plays an ongoing modulatory role in the adult. © 2011 Wang et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wang, T
Molliver, DCdcm12@pitt.eduDCM12
Jing, X
Schwartz, ES
Yang, FC
Samad, OA
Ma, Q
Davis, BMbmd1@pitt.eduBMD1
ContributionContributors NameEmailPitt UsernameORCID
Date: 21 December 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0028908
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
School of Medicine > Anesthesiology
Refereed: Yes
MeSH Headings: Animals; Base Sequence; Cells, Cultured; Core Binding Factor Alpha 2 Subunit--genetics; Core Binding Factor Alpha 2 Subunit--metabolism; DNA Primers; Glial Cell Line-Derived Neurotrophic Factor Receptors--genetics; Glial Cell Line-Derived Neurotrophic Factor Receptors--metabolism; In Situ Hybridization; Mice; Peripheral Nervous System--injuries; Peripheral Nervous System--physiopathology; Phenotype; RNA, Messenger--genetics; Real-Time Polymerase Chain Reaction; Sensory Receptor Cells--physiology; Skin--innervation; Skin--physiopathology; TRPV Cation Channels--metabolism; Up-Regulation
Other ID: NLM PMC3244441
PubMed Central ID: PMC3244441
PubMed ID: 22216140
Date Deposited: 07 Sep 2012 19:36
Last Modified: 02 Feb 2019 16:56


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