GFRα3, a Component of the Artemin Receptor, Is Required for Migration and Survival of the Superior Cervical Ganglion

Nishino, Jinsuke; Mochida, Kyoko; Ohfuji, Yasuhisa; Shimazaki, Takuya; Meno, Chikara; Oh‐ishi, Sachiko; Matsuda, Yoichi; Fujii, Hideyuki; Saijoh, Yukio; Hamada, Hiroshi

doi:10.1016/s0896-6273(01)80031-3

Cited by 114 publications

(117 citation statements)

References 46 publications

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“…To our knowledge, this study is the first rigorous report of nociception in mice lacking GFRα3, and our results are consistent with prior studies that found no discernable phenotype in peripheral sensory ganglia in both artemin and GFRα3-null mice (17,18). The lack of any salient somatosensory abnormalities in naïve Gfrα3 −/− mice suggests that the receptor has no substantial role in sensory nervous system development, despite the fact that it is expressed in ∼20% of adult DRG neurons.…”

Section: Discussionsupporting

confidence: 91%

“…S5 E and F) were similar between genotypes. These results show that the development of DRG neurons is not influenced by GFRα3 signaling, results consistent with prior analyses of these mice as well as those lacking artemin expression (17,18).…”

Section: Significancesupporting

confidence: 91%

“…The NGF/TrkA signaling pathways and their requirement in sensory neuron development and sensitization are well-established (1), but how GFRα receptors induce sensory neuron sensitization is poorly understood. Therefore, to determine how artemin leads to cold pain, we first examined acute sensitivity of mice lacking the artemin receptor GFRα3 (Gfrα3 −/− ) to thermal or mechanical stimuli, which to the best of our knowledge, has not been reported for these animals (17,18). Using the cold plantar (19), von Frey (mechanical), and Hargreaves (radiant heat) assays, we compared thermal and mechanically evoked behaviors of WT and Gfrα3 −/− mouse littermates, finding no differences between the two genotypes (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFRα3 signaling can be targeted to selectively treat cold pain.W hen pain continues past its usefulness as a warning of potential tissue damage, it becomes a debilitating condition for which few viable treatments are currently available. The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2-5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1). These substances are released locally at the site of injury by infiltrating immune cells, such as macrophages, neutrophils, and T cells, as well as resident cells, including keratinocytes and mast cells (6), and either directly activate sensory receptors or sensitize them to subsequent stimuli (7). Moreover, prolonged inflammation can lead to central sensitization (in the spinal cord and brain) and bring about long-lasting chronic pain that persists after acute inflammation has resolved. Thus, a better understanding of the molecules involved in neuroinflammation may lead to therapeutic options for acute and chronic pain.Of the range of proalgesics known to promote pain, only nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor family ligand (GFL) artemin have been shown to lead to cold hypersensitivity (8-11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface rece...

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Section: Discussionsupporting

confidence: 91%

Section: Significancesupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…corresponding phenotypes of ligand and/or receptor mouse knockouts (31,32). In summary, GDNF, NTN, EVN/ART, and PSP are part of a neurotrophic signaling system whereby specific high affinity ligand-binding subunits (GFR␣-1 to GFR␣-4) can interact with the same tyrosine kinase subunit (cRET) to elicit functional responses in neuronal cells.…”

Section: /Ebi Data Bank With Accession Number(s) Aj294475 (For Rat Gfmentioning

confidence: 99%

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

Masure¹,

Cik²,

Hoefnagel³

et al. 2000

Journal of Biological Chemistry

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Four members of the glial cell line-derived neurotrophic factor family have been identified (GDNF, neurturin, persephin, and enovin/artemin). They bind to a specific membrane-anchored GDNF family receptor as follows: GFR␣-1 for GDNF, GFR␣-2 for neurturin, GFR␣-3 for enovin/artemin, and (chicken) GFR␣-4 for persephin. Subsequent signaling occurs through activation of a common transmembrane tyrosine kinase, cRET. GFR␣-4, the coreceptor for persephin, was previously identified in chicken only. We describe the cloning and characterization of a mammalian persephin receptor GFR␣-4. The novel GFR␣ receptor is substantially different in sequence from all known GFR␣s, including chicken GFR␣-4, and lacks the first cysteine-rich domain present in all previously characterized GFR␣s. At least two different GFR␣-4 splice variants exist in rat tissues, differing at their respective COOH termini. GFR␣-4 mRNA is expressed at low levels in different brain areas in the adult as well as in some peripheral tissues including testis and heart. Recombinant rat GFR␣-4 variants were expressed in mammalian cells and shown to be at least partially secreted from the cells. Persephin binds specifically and with high affinity (K D ‫؍‬ 6 nM) to the rat GFR␣-4 receptor, but no cRET activation could be demonstrated. Although the newly characterized mammalian GFR␣-4 receptor is structurally divergent from previously characterized GFR␣ family members, we suggest that it is a mammalian orthologue of the chicken persephin receptor. This discovery will allow a more detailed investigation of the biological targets of persephin action and its potential involvement in diseases of the nervous system.

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“…However, examination of fixed embryos has shown that the superior cervical ganglion forms from cells that first migrate ventrally to form a column of cells that is continuous with the stellate ganglion primordium at lower cervical levels; some cells subsequently migrate rostrally to form the superior cervical ganglion (Rubin, 1985). This rostral migration occurs between E12.5 and E14.5 in mice (Nishino et al, 1999;Enomoto et al, 2001). It would be interesting to examine the phenotype and the mode of migration of the cells that migrate rostrally to form the superior cervical ganglion.…”

Section: Differentiation and Cell Migrationmentioning

confidence: 99%

The migratory behavior of immature enteric neurons

Hao

Anderson

Kobayashi

et al. 2008

Developmental Neurobiology

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While they are migrating caudally along the developing gut, around 10%-20% of enteric neural crest-derived cells start to express pan-neuronal markers and tyrosine hydroxylase (TH). We used explants of gut from embryonic TH-green fluorescence protein (GFP) mice and time-lapse microscopy to examine whether these immature enteric neurons migrate and their mode of migration. In the gut of E10.5 and E11.5 TH-GFP mice, around 50% of immature enteric neurons (GFP + cells) migrated, with an average speed of around 15 lm/h. This is slower than the speed at which the population of enteric neural crest-derived cells advances along the developing gut, and hence neuronal differentiation seems to slow, but not necessarily halt, the caudal migration of enteric neural crest cells. Most migrating immature enteric neurons migrated caudally by extending a long-leading process followed by translocation of the cell body. This mode of migration is different from that of non-neuronal enteric neural crestderived cells and neural crest cells in other locations, but resembles that of migrating neurons in many regions of the developing central nervous system (CNS). In migrating immature enteric neurons, a swelling often preceded the movement of the nucleus in the direction of the leading process. However, the centrosomal marker, pericentrin, was not localized to either the leading process or swelling. This seems to be the first detailed report of neuronal migration in the developing mammalian peripheral nervous system. ' 2008 Wiley Periodicals, Inc. Develop Neurobiol 69: 22-35, 2009

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GFRα3, a Component of the Artemin Receptor, Is Required for Migration and Survival of the Superior Cervical Ganglion

Cited by 114 publications

References 46 publications

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

The migratory behavior of immature enteric neurons

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