Genomes and Genes
Gene Symbol: Gfra2
Description: glial cell line derived neurotrophic factor family receptor alpha 2
Alias: GDNF family receptor alpha-2, GDNF receptor beta, GDNFR-alpha-2, GDNFR-beta, GFR alpha 2, NRTNR-alpha, NTNR-alpha, TGF-beta-related neurotrophic factor receptor 2, neurturin receptor alpha
- Jing S, Yu Y, Fang M, Hu Z, Holst P, Boone T, et al. GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem. 1997;272:33111-7 pubmed..Consistent with a role in GDNF function, the GFRalphas and Ret are expressed in many of the same tissues, suggesting that GFRalphas mediate the action of GDNF family ligands in vivo. ..
- McDonagh S, Lee J, Izzo A, Brubaker P. Role of glial cell-line derived neurotropic factor family receptor alpha2 in the actions of the glucagon-like peptides on the murine intestine. Am J Physiol Gastrointest Liver Physiol. 2007;293:G461-8 pubmed..Together, these findings demonstrate a role for GFRalpha2-expressing enteric neurons in the downstream signaling of the glucagon-like peptides to inhibit GI motility, but not in intestinal growth. ..
- Holm P, Rodriguez F, Kresse A, Canals J, Silos Santiago I, Arenas E. Crucial role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons. Development. 2003;130:3535-45 pubmed..In summary, our findings suggest that, unlike NT3 and GDNF, TrkB ligands are required and sufficient to promote the development of central noradrenergic neurons. ..
- Perez Millan M, Brinkmeier M, Mortensen A, Camper S. PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells. elife. 2016;5: pubmed publisher..Zeb2 activation appears to be a key step in the EMT process. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation. ..
- Lippoldt E, Elmes R, McCoy D, Knowlton W, McKemy D. Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci. 2013;33:12543-52 pubmed publisher..These results show for the first time that only select neurotrophic factors induce cold sensitization through TRPM8 in vivo, unlike the broad range of proalgesic agents capable of promoting heat hyperalgesia. ..
- Paveliev M, Airaksinen M, Saarma M. GDNF family ligands activate multiple events during axonal growth in mature sensory neurons. Mol Cell Neurosci. 2004;25:453-9 pubmed..We also show that neurturin and GDNF induce extensive lamellipodia formation on neuronal somata and growth cones. GDNF, when applied after the time of axonal initiation in culture, also promotes axonal elongation. ..
- Bolon B, Jing S, Asuncion F, Scully S, Pisegna M, Van G, et al. The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction. Toxicol Pathol. 2004;32:275-94 pubmed
- Fundin B, Mikaels A, Westphal H, Ernfors P. A rapid and dynamic regulation of GDNF-family ligands and receptors correlate with the developmental dependency of cutaneous sensory innervation. Development. 1999;126:2597-610 pubmed
- Botchkareva N, Botchkarev V, Welker P, Airaksinen M, Roth W, Suvanto P, et al. New roles for glial cell line-derived neurotrophic factor and neurturin: involvement in hair cycle control. Am J Pathol. 2000;156:1041-53 pubmed
- Lindahl M, Timmusk T, Rossi J, Saarma M, Airaksinen M. Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development. Mol Cell Neurosci. 2000;15:522-33 pubmed..Finally, in human, GFRalpha4 expression may restrict the inherited cancer syndrome multiple endocrine neoplasia type 2, associated with mutations in RET, to these cells. ..
- Garces A, Haase G, Airaksinen M, Livet J, Filippi P, Delapeyriere O. GFRalpha 1 is required for development of distinct subpopulations of motoneuron. J Neurosci. 2000;20:4992-5000 pubmed..on embryonic mouse spinal cord, we demonstrate that whereas Ret is expressed by nearly all motoneurons, Gfra1 and Gfra2 exhibit complex and distinct patterns of expression...
- Rossi J, Tomac A, Saarma M, Airaksinen M. Distinct roles for GFRalpha1 and GFRalpha2 signalling in different cranial parasympathetic ganglia in vivo. Eur J Neurosci. 2000;12:3944-52 pubmed..Gfra1 mRNA was expressed at E12 but not in newborn cranial parasympathetic ganglia, while Gfra2 mRNA and protein were strongly expressed in newborn and adult cranial parasympathetic neurons and their ..
- Gianino S, Grider J, Cresswell J, Enomoto H, Heuckeroth R. GDNF availability determines enteric neuron number by controlling precursor proliferation. Development. 2003;130:2187-98 pubmed..All of these heterozygous mice, however, have striking problems with intestinal contractility and neurotransmitter release, demonstrating that Ret signaling is critical for both ENS structure and function. ..
- Mikaels A, Livet J, Westphal H, de Lapeyriere O, Ernfors P. A dynamic regulation of GDNF-family receptors correlates with a specific trophic dependency of cranial motor neuron subpopulations during development. Eur J Neurosci. 2000;12:446-56 pubmed..Our results indicate that specific GDNF family ligands support selective muscle-motor neuron circuits during development. ..
- Fame R, Dehay C, Kennedy H, Macklis J. Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex. Cereb Cortex. 2017;27:1817-1830 pubmed publisher..Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships. ..
- Naveilhan P, Baudet C, Mikaels A, Shen L, Westphal H, Ernfors P. Expression and regulation of GFRalpha3, a glial cell line-derived neurotrophic factor family receptor. Proc Natl Acad Sci U S A. 1998;95:1295-300 pubmed..The unique complementary and overlapping expression of gfralpha3 implies distinct functions in the developing and adult mouse from that of GFRalpha1 and GFRalpha2. ..
- Voikar V, Rossi J, Rauvala H, Airaksinen M. Impaired behavioural flexibility and memory in mice lacking GDNF family receptor alpha2. Eur J Neurosci. 2004;20:308-12 pubmed..The results suggest that GFRalpha2 signalling plays a role in the development or maintenance of cognitive abilities that help in solving complex learning tasks. ..
- Vohra B, Planer W, Armon J, Fu M, Jain S, Heuckeroth R. Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis. Dev Dyn. 2007;236:106-17 pubmed..5 male RetDN heterozygous mouse gut explants in organ culture significantly increased the rate of ENS precursor migration through the bowel. ..
- Wanigasekara Y, Airaksinen M, Heuckeroth R, Milbrandt J, Keast J. Neurturin signalling via GFRalpha2 is essential for innervation of glandular but not muscle targets of sacral parasympathetic ganglion neurons. Mol Cell Neurosci. 2004;25:288-300 pubmed..Our results indicate that neurturin, acting through GFRalpha2, is essential for parasympathetic innervation of the mucosae of reproductive organs, as well as for maintenance of a broader group of sacral parasympathetic neurons. ..
- Suvanto P, Wartiovaara K, Lindahl M, Arumae U, Moshnyakov M, Horelli Kuitunen N, et al. Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell line-derived neurotrophic factor receptor beta, a homologue to GDNFR-alpha. Hum Mol Genet. 1997;6:1267-73 pubmed..The distinct tissue distribution of GDNFR-beta mRNA and its ability to mediate GDNF signal in transfected cells suggest a role in signal transduction of GDNF and, possibly, related neurotrophic factors in vivo. ..
- Nishino J, Mochida K, Ohfuji Y, Shimazaki T, Meno C, Ohishi S, et al. GFR alpha3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron. 1999;23:725-36 pubmed..These observations suggest that GFR alpha3-mediated signaling is required both for the rostral migration of SCG precursors and for the survival of mature SCG neurons. ..
- Wong Y, Too H. Identification of mammalian GFRalpha-2 splice isoforms. Neuroreport. 1998;9:3767-73 pubmed..The identity of these isoforms were further confirmed by the isolation of the gene and the characterisation of the splice junctions. ..
- Kupari J, Airaksinen M. Different requirements for GFRÎ±2-signaling in three populations of cutaneous sensory neurons. PLoS ONE. 2014;9:e104764 pubmed publisher..In addition, the observation that the large Ret-positive DRG neurons lack GFRÎ±2 immunoreactivity in mature animals suggests that these neurons switch their GFRÎ± signaling pathways during postnatal development. ..
- Widenfalk J, Tomac A, Lindqvist E, Hoffer B, Olson L. GFRalpha-3, a protein related to GFRalpha-1, is expressed in developing peripheral neurons and ensheathing cells. Eur J Neurosci. 1998;10:1508-17 pubmed
- Ishida H, Saba R, Kokkinopoulos I, Hashimoto M, Yamaguchi O, Nowotschin S, et al. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway. Cell Rep. 2016;16:1026-1038 pubmed publisher..containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs...
- Brantley M, Jain S, Barr E, Johnson E, Milbrandt J. Neurturin-mediated ret activation is required for retinal function. J Neurosci. 2008;28:4123-35 pubmed publisher..These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice. ..
- Lindfors P, Lindahl M, Rossi J, Saarma M, Airaksinen M. Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice. Endocrinology. 2006;147:2237-44 pubmed..In conclusion, this study indicates a novel role for endogenous GFRalpha4 signaling in regulating calcitonin production in thyroid C cells of young mice. ..
- Fleming M, Vysochan A, PaixÃ£o S, Niu J, Klein R, Savitt J, et al. Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors. elife. 2015;4:e06828 pubmed publisher..Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling. ..
- Rossi J, Herzig K, Voikar V, Hiltunen P, Segerstrale M, Airaksinen M. Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2. J Clin Invest. 2003;112:707-16 pubmed..Why GFRalpha2-deficient (Gfra2-/-) mice grow poorly has remained unclear...
- Rossi J, Santamäki P, Airaksinen M, Herzig K. Parasympathetic innervation and function of endocrine pancreas requires the glial cell line-derived factor family receptor alpha2 (GFRalpha2). Diabetes. 2005;54:1324-30 pubmed..The GFRalpha2-KO mouse represents a useful model to study the role of parasympathetic innervation of the endocrine pancreas in glucose homeostasis. ..
- Lee C, Tee L, Dusenbery S, Takata T, Golden J, Pierchala B, et al. Neurotrophin and GDNF family ligands promote survival and alter excitotoxic vulnerability of neurons derived from murine embryonic stem cells. Exp Neurol. 2005;191:65-76 pubmed..These findings demonstrate that the response of ES-derived neurons to neurotrophins and GDNF family ligands is largely similar to that of other cultured central neurons. ..
- Hiltunen P, Airaksinen M. Sympathetic cholinergic target innervation requires GDNF family receptor GFR alpha 2. Mol Cell Neurosci. 2004;26:450-7 pubmed..Thus, neurturin may be a general target-derived innervation factor for postganglionic cholinergic neurons in all parts of the autonomic nervous system. ..
- Baloh R, Tansey M, Golden J, Creedon D, Heuckeroth R, Keck C, et al. TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron. 1997;18:793-802 pubmed..Comparative analysis of TrnR1, TrnR2, and Ret expression indicates that multiple receptor complexes, capable of mediating GDNF and NTN signaling, exist in vivo. ..
- Enomoto H, Heuckeroth R, Golden J, Johnson E, Milbrandt J. Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin. Development. 2000;127:4877-89 pubmed
- Heuckeroth R, Enomoto H, Grider J, Golden J, Hanke J, Jackman A, et al. Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron. 1999;22:253-63 pubmed..The loss of GFR alpha2-expressing neurons, in conjunction with earlier studies, provides strong support for GFR alpha2/Ret receptor complexes as the critical mediators of NTN function in vivo. ..
- Luukko K, Suvanto P, Saarma M, Thesleff I. Expression of GDNF and its receptors in developing tooth is developmentally regulated and suggests multiple roles in innervation and organogenesis. Dev Dyn. 1997;210:463-71 pubmed..Taken together, these results suggest that GDNF acts as a target-derived neurotrophic factor during tooth innervation. In addition, GDNF and its receptors may have nonneuronal organogenetic functions during tooth morphogenesis. ..
- Muñoz Bravo J, Hidalgo Figueroa M, Pascual A, Lopez Barneo J, Leal Cerro A, Cano D. GDNF is required for neural colonization of the pancreas. Development. 2013;140:3669-79 pubmed publisher..Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas. ..
- Rosenthal A. The GDNF protein family: gene ablation studies reveal what they really do and how. Neuron. 1999;22:201-3 pubmed
- Almeida A, Arroz Madeira S, Fonseca Pereira D, Ribeiro H, Lasrado R, Pachnis V, et al. RET/GFR? signals are dispensable for thymic T cell development in vivo. PLoS ONE. 2012;7:e52949 pubmed publisher..We show that Ret, Gfra1 and Gfra2 are abundantly expressed by foetal and adult immature DN thymocytes...
- Pozas E, Ibanez C. GDNF and GFRalpha1 promote differentiation and tangential migration of cortical GABAergic neurons. Neuron. 2005;45:701-13 pubmed..The lack of involvement of RET or NCAM in these processes suggests the existence of additional transmembrane effectors for GDNF. ..
- Hiltunen J, Laurikainen A, Airaksinen M, Saarma M. GDNF family receptors in the embryonic and postnatal rat heart and reduced cholinergic innervation in mice hearts lacking ret or GFRalpha2. Dev Dyn. 2000;219:28-39 pubmed..b>Gfra2 was expressed in the outer layers of the aorta and pulmonary trunk and in the valves at E18-P60...
- Lähteenmäki M, Kupari J, Airaksinen M. Increased apoptosis of parasympathetic but not enteric neurons in mice lacking GFRalpha2. Dev Biol. 2007;305:325-32 pubmed
- Oppenheim R, Houenou L, Parsadanian A, Prevette D, Snider W, Shen L. Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: regulation of programmed cell death among motoneuron subtypes. J Neurosci. 2000;20:5001-11 pubmed..GDNF-dependent and -independent MNs may reflect subtypes with distinct synaptic targets and afferent inputs. ..
- Baudet C, Mikaels A, Westphal H, Johansen J, Johansen T, Ernfors P. Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins. Development. 2000;127:4335-44 pubmed..At late postnatal stages, ART prevents survival elicited by GDNF and NTN. These data provide new insights on the roles of GDNF family ligands in sensory neuron development. ..
- Nanobashvili A, Airaksinen M, Kokaia M, Rossi J, Asztely F, Olofsdotter K, et al. Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor alpha 2. Proc Natl Acad Sci U S A. 2000;97:12312-7 pubmed..that epileptogenesis, as assessed in the hippocampal kindling model, is markedly suppressed in mice lacking GFR alpha 2. Moreover, at 6 to 8 wk after having reached the epileptic state, the hyperexcitability is lower in GFR alpha 2 ..
- Nanobashvili A, Kokaia Z, Lindvall O. Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2. Neuroscience. 2003;118:845-52 pubmed..Our findings provide evidence that signaling through the GFRalpha2 receptor contributes to seizure generalization in rapid kindling. ..
- Jomary C, Thomas M, Grist J, Milbrandt J, Neal M, Jones S. Expression patterns of neurturin and its receptor components in developing and degenerative mouse retina. Invest Ophthalmol Vis Sci. 1999;40:568-74 pubmed..These results suggest that NTN and its receptor are involved in retinal postnatal development and maintenance and that alterations in their transcription patterns are associated with inherited retinal degeneration. ..
- Too H. Real time PCR quantification of GFRalpha-2 alternatively spliced isoforms in murine brain and peripheral tissues. Brain Res Mol Brain Res. 2003;114:146-53 pubmed..The preferred receptor for NTN is the GDNF family receptor alpha 2 (GFRalpha-2)...
- Gorokhova S, Gaillard S, Urien L, Malapert P, Legha W, Baronian G, et al. Uncoupling of molecular maturation from peripheral target innervation in nociceptors expressing a chimeric TrkA/TrkC receptor. PLoS Genet. 2014;10:e1004081 pubmed publisher..Moreover, adult homozygous TrkAC knock-in mice displayed severe deficits in acute and tissue injury-induced pain, representing the first viable adult Trk mouse mutant with a pain phenotype. ..
- Luukko K, Saarma M, Thesleff I. Neurturin mRNA expression suggests roles in trigeminal innervation of the first branchial arch and in tooth formation. Dev Dyn. 1998;213:207-19 pubmed..In addition, although NTN appears not to be directly involved in the regulation of tooth morphogenesis, it may have non-neuronal, organogenetic functions during tooth formation. ..
- Cobb J, Duboule D. Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia. Development. 2005;132:3055-67 pubmed..e. the digits and the penis/clitoris. ..
- Kupari J, Rossi J, Herzig K, Airaksinen M. Lack of cholinergic innervation in gastric mucosa does not affect gastrin secretion or basal acid output in neurturin receptor GFR?2 deficient mice. J Physiol. 2013;591:2175-88 pubmed publisher..Basal acid secretion in the KO mice appears to be, at least partly, facilitated by constitutive activity of muscarinic receptors. ..
- Baloh R, Gorodinsky A, Golden J, Tansey M, Keck C, Popescu N, et al. GFRalpha3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proc Natl Acad Sci U S A. 1998;95:5801-6 pubmed..Fibroblasts expressing Ret and GFRalpha3 do not respond to any of the known members of the GDNF family, suggesting that GFRalpha3 interacts with an unknown ligand or requires a different or additional signaling protein to function. ..
- Worby C, Vega Q, Chao H, Seasholtz A, Thompson R, Dixon J. Identification and characterization of GFRalpha-3, a novel Co-receptor belonging to the glial cell line-derived neurotrophic receptor family. J Biol Chem. 1998;273:3502-8 pubmed..Comparison of the expression patterns of GFRalpha-3 and Ret suggests that these molecules could form a receptor pair and interact with GDNF family members to play unique roles in development. ..
- Widenfalk J, Nosrat C, Tomac A, Westphal H, Hoffer B, Olson L. Neurturin and glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta), novel proteins related to GDNF and GDNFR-alpha with specific cellular patterns of expression suggesting roles in the developing and adult nervous system and in peri. J Neurosci. 1997;17:8506-19 pubmed..Although NTN and GDNFR-beta expression patterns are sometimes complementary, this is not always the case, suggesting multiple modi operandi of GDNF and NTN in relation to RET and the two binding proteins, GDNFR-alpha and GDNFR-beta. ..
- Chen Z, Donnelly C, Dominguez B, Harada Y, Lin W, Halim A, et al. p75 Is Required for the Establishment of Postnatal Sensory Neuron Diversity by Potentiating Ret Signaling. Cell Rep. 2017;21:707-720 pubmed publisher..These results suggest that p75 is required for the development of the nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. ..