Ret-Dependent and Ret-Independent Mechanisms of Gfl-Induced Sensitization

Schmutzler, Brian S.; Roy, Shannon; Pittman, Sherry K.; Meadows, Rena M.; Hingtgen, Cynthia M.

doi:10.1186/1744-8069-7-22

Cited by 30 publications

(21 citation statements)

References 63 publications

(114 reference statements)

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“…Single-cell RT-PCR was conducted as previously described (Malin et al, 2011; Schwartz et al 2011; Wang et al, 2011). Cutaneous afferents were retrogradely labeled by subcutaneous injection of 10 μl of IB 4 -488 (2 μg/μl) on the dorsal-medial side of the hind paw.…”

Section: Methodsmentioning

confidence: 99%

Neurturin Overexpression in Skin Enhances Expression of TRPM8 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Cool and Menthol

et al. 2013

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Neurturin (NRTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands that exerts its actions via Ret tyrosine kinase and GFRα2. Expression of the Ret/GFRα2 co-receptor complex is primarily restricted to the peripheral nervous system and is selectively expressed by sensory neurons that bind the isolectin B4 (IB4). To determine how target-derived NRTN affects sensory neuron properties, transgenic mice that overexpress NRTN in keratinocytes (NRTN-OE mice) were analyzed. Overexpression of NRTN increased the density of PGP9.5-positive, but not calcitonin gene-related peptide (CGRP)-positive, free nerve endings in footpad epidermis. GFRα2- immunopositive somata were hypertrophied in NRTN-OE mice. Electron microscopic analysis further revealed hypertrophy of unmyelinated sensory axons and a subset of myelinated axons. Overexpression of NRTN increased the relative level of mRNAs encoding GFRα2 and Ret, the ATP receptor P2X3 (found in IB4-positive, GFRα2-expressing sensory neurons), the acid-sensing ion channel (ASIC) 2a, and transient receptor potential cation channel subfamily member M8 (TRPM8) in sensory ganglia. Behavioral testing of NRTN-OE mice revealed an increased sensitivity to mechanical stimuli in glabrous skin of the hind paw. NRTN-OE mice also displayed increased behavioral sensitivity to cool temperature (17°C-20°C) and oral sensitivity to menthol. The increase in cool and menthol sensitivity correlated with a significant increase in TRPM8 expression and the percentage of menthol-responsive cutaneous sensory neurons. These data indicate that the expression level of NRTN in the skin modulates gene expression in cutaneous sensory afferents and behavioral sensitivity to thermal, chemical and mechanical stimuli.

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Section: Methodsmentioning

confidence: 99%

Neurturin Overexpression in Skin Enhances Expression of TRPM8 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Cool and Menthol

et al. 2013

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“…The efficacy of Sprr1a siRNAs was established using 4d-old cultures of DRG neurons transfected with 50nM non-targeting siRNA or a Smartpool of Sprr1a targeting siRNAs (Dharmacon; Thermo Fisher Scientific, Lafayette, CO) using Metafectine reagent (Biontex, Martinsried, Germany) following the general protocol described in (Schmutzler, et al, 2011). Cells were incubated 48h with siRNAs, total protein was isolated and western blotting performed using anti-Sprr1a (1:1000, a kind gift from Dr. Stephen Strittmatter, Yale University, New Haven, CT)(Bonilla, et al, 2002)).…”

Section: Methodsmentioning

confidence: 99%

The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a

Jing

Wang

Huang

et al. 2012

Experimental Neurology

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Factors that enhance the intrinsic growth potential of adult neurons are key players in the successful repair and regeneration of neurons following injury. Injury-induced activation of transcription factors has a central role in this process because they regulate expression of regeneration-associated genes. Sox11 is a developmentally expressed transcription factor that is significantly induced in adult neurons in response to injury. Its function in injured neurons is however undefined. Here, we report studies that use herpes simplex virus (HSV)-vector-mediated expression of Sox11 in adult sensory neurons to assess the effect of Sox11 overexpression on neuron regeneration. Cultured mouse dorsal root ganglia (DRG) neurons transfected with HSV-Sox11 exhibited increased neurite elongation and branching relative to naïve and HSV-vector control treated neurons. Neurons from mice injected in foot skin with HSV-Sox11 exhibited accelerated regeneration of crushed saphenous nerves as indicated by faster regrowth of axons and nerve fibers to the skin, increased myelin thickness and faster return of nerve and skin sensitivity. Downstream targets of HSV-Sox11 were examined by analyzing changes in gene expression of known regeneration-associated genes. This analysis in combination with mutational and chromatin immunoprecipitation assays indicates that the ability of Sox11 to accelerate in vivo nerve regeneration is dependent on its transcriptional activation of the regeneration-associated gene, small proline rich protein 1a (Sprr1a). This finding reveals a new functional linkage between Sox11 and Sprr1a in adult peripheral neuron regeneration.

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“…All GFRα receptors are anchored to the cell plasma membrane through a glycosyl phosphatidylinositol (GPI) link [8]. GFLs are also able to signal in a RETindependent way and, among others, utilize the neural cell adhesion molecule (NCAM) as an alternative signaling receptor [9].…”

Section: Gfls and Their Receptorsmentioning

confidence: 99%

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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Introduction: GDNF and its family of ligands (GFLs) have several functions in the nervous system. As a survival factor for dopaminergic neurons, GDNF was used in clinical trials for Parkinson's disease. However, GFLs their receptors are potential targets for new pain-controlling drugs. Such a potential should not be underestimated because molecules with analgesic activities in rodents mostly failed to be effective in translational studies. Areas covered:The circuitry, molecular and cellular mechanisms by which GFLs control nociception, their intervention in inflammatory and neuropathic pain, the problems related to effective GDNF delivery to the brain, the possibility to target the GFL receptor complex rather than its ligands, also by the use of non-peptidyl agonists, are discussed. Expert opinion:In nociceptive pathways, an ideal drug should either: i. Target the release of endogenous GFLs from large dense-cored vesicles (LGVs) by acting e.g. onto the phosphatidylinositol-3-phosphate [PtdIns(3)P] pool, which is sensitive to Ca 2+ modulation; ii. Target the GFL receptor complex. Besides to XIB403, a thiol molecule that enhances GFRα family receptor signaling, existing drugs such as retinoic acid and amitriptyline should be considered for effective targeting of GDNF, at least in neuropathic pain. The approach of pain modeling in experimental animals is discussed.

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Ret-Dependent and Ret-Independent Mechanisms of Gfl-Induced Sensitization

Cited by 30 publications

References 63 publications

Neurturin Overexpression in Skin Enhances Expression of TRPM8 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Cool and Menthol

Neurturin Overexpression in Skin Enhances Expression of TRPM8 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Cool and Menthol

The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

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