Four different ligand-receptor binding pairs of the GDNF (glial cell line-derived neurotrophic factor) family exist in mammals, and they all signal via the transmembrane RET receptor tyrosine kinase. In addition, GRAL (GDNF Receptor Alpha-Like) protein of unknown function and Gas1 (growth arrest specific 1) have GDNF family receptor (GFR)-like domains. Orthologs of the four GFRα receptors, GRAL and Gas1 are present in all vertebrate classes. In contrast, although bony fishes have orthologs of all four GDNF family ligands (GFLs), one of the ligands, neurturin, is absent in clawed frog and another, persephin, is absent in the chicken genome. Frog GFRα2 has selectively evolved possibly to accommodate GDNF as a ligand. The key role of GDNF and its receptor GFRα1 in enteric nervous system development is conserved from zebrafish to humans. The role of neurturin, signaling via GFRα2, for parasympathetic neuron development is conserved between chicken and mice. The role of artemin and persephin that signal via GFRα3 and GFRα4, respectively, is unknown in non-mammals. The presence of RET- and GFR-like genes in insects suggests that a ProtoGFR and a ProtoRET arose early in the evolution of bilaterian animals, but when the ProtoGFL diverged from existing transforming growth factor (TGFβ)-like proteins remains unclear. The four GFLs and GFRαs were presumably generated by genome duplications at the origin of vertebrates. Loss of neurturin in frog and persephin in chicken suggests functional redundancy in early tetrapods. Functions of non-mammalian GFLs and prechordate RET and GFR-like proteins remain to be explored.

1.
Abrescia C, Sjöstrand D, Kjær S, Ibáñez CF (2005) Drosophila RET contains an active tyrosine kinase and elicits neurotrophic activities in mammalian cells. FEBS Lett 579:3789–3796.
2.
Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nature Rev Neurosci 3:383–394.
3.
Amiel J, Lyonnet S (2001) Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet 38:729–739.
4.
Amoresano A, Incoronato M, Monti G, Pucci P, de Franciscis V, Cerchia L (2005) Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal 17:717–727.
5.
Anders J, Kjær S, Ibáñez CF (2001) Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J Biol Chem 276:35808–35817.
6.
Baloh RH, Enomoto H, Johnson EM Jr, Milbrandt J (2000a) The GDNF family ligands and receptors – implications for neural development. Curr Opin Neurobiol 10:103–110.
7.
Baloh RH, Tansey MG, Johnson EM Jr, Milbrandt J (2000b) Functional mapping of receptor specificity domains of glial cell line-derived neurotrophic factor (GDNF) family ligands and production of GFRα1 RET-specific agonists. J Biol Chem 275:3412–3420.
8.
Barlow A, de Graaff E, Pachnis V (2003) Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron 40:905–916.
9.
Benito-Gutierrez E, Nake C, Llovera M, Comella JX, Garcia-Fernandez J (2005) The single AmphiTrk receptor highlights increased complexity of neurotrophin signalling in vertebrates and suggests an early role in developing sensory neuroepidermal cells. Development 132:2191–2202.
10.
Bilak MM, Shifrin DA, Corse AM, Bilak SR, Kuncl RW (1999) Neuroprotective utility and neurotrophic action of neurturin in postnatal motor neurons: comparison with GDNF and persephin. Mol Cell Neurosci 13:326–336.
11.
Bisgrove BW, Raible DW, Walter V, Eisen JS, Grunwald DJ (1997) Expression of c-ret in the zebrafish embryo: potential roles in motoneuronal development. J Neurobiol 33:749–768.
12.
Brodski C, Schaubmar A, Dechant G (2002) Opposing functions of GDNF and NGF in the development of cholinergic and noradrenergic sympathetic neurons. Mol Cell Neurosci 19:528–538.
13.
Brunet JF, Pattyn A (2002) Phox2 genes – from patterning to connectivity. Curr Opin Genet Dev 12:435–440.
14.
Burau K, Stenull I, Huber K, Misawa H, Berse B, Unsicker K, Ernsberger U (2004) c-ret regulates cholinergic properties in mouse sympathetic neurons: evidence from mutant mice. Eur J Neurosci 20:353–362.
15.
Cabrera JR, Sanchez-Pulido L, Rojas AM, Valencia A, Manes S, Naranjo JR, Mellstrom B (2006) Gas1 is related to the GDNF family receptors alpha and regulates Ret signaling. J Biol Chem (in press).
16.
Cacalano G, Farinas I, Wang LC, Hagler K, Forgie A Moore M, Armanini M, Phillips H, Ryan AM, Reichardt LF, Hynes M, Davies A, Rosenthal A (1998) GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21:53–62.
17.
Chang H, Brown CW, Matzuk MM (2002) Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 23:787–823.
18.
Chen J, Butowt R, Rind HB, von Bartheld CS (2003) GDNF increases the survival of developing oculomotor neurons through a target-derived mechanism. Mol Cell Neurosci 24:41–56.
19.
Del Sal G, Ruaro ME, Philipson L, Schneider C (1992) The growth arrest-specific gene, gas1, is involved in growth suppression. Cell 70:595–607.
20.
Drawbridge J, Meighan CM, Mitchell EA (2000) GDNF and GFRalpha-1 are components of the axolotl pronephric duct guidance system. Dev Biol 228:116–124.
21.
Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M, Sariola H, Pachnis V (1996) GDNF signalling through the Ret receptor tyrosine kinase. Nature 381:789–793.
22.
Eigenbrot C, Gerber N (1997) X-ray structure of glial cell-derived neurotrophic factor at 1.9 A resolution and implications for receptor binding. Nat Struct Biol 4:435–438.
23.
Eketjäll S, Fainzilber M, Murray-Rust J, Ibáñez CF (1999) Distinct structural elements in GDNF mediate binding to GFRα1 and activation of the GFRα1-c-Ret receptor complex. EMBO J 18:5901–5910.
24.
Elworthy S, Pinto JP, Pettifer A, Cancela ML, Kelsh RN (2005) Phox2b function in the enteric nervous system is conserved in zebrafish and is sox10-dependent. Mech Dev 122:659–669.
25.
Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME, Cutler DJ, Green ED, Chakravarti A (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434:857–863.
26.
Enokido Y, de Sauvage F, Hongo JA, Ninkina N, Rosenthal A, Buchman VL, Davies AM (1998) GFRα-4 and the tyrosine kinase Ret form a functional receptor complex for persephin. Curr Biol 8:1019–1022.
27.
Enomoto H (2005) Regulation of neural development by glial cell line-derived neurotrophic factor family ligands. Anat Sci Int 80:42–52.
28.
Enomoto H, Araki T, Jackman A, Heuckeroth RO, Snider WD, Johnson EM Jr, Milbrandt J (1998) GFRa1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21:317–324.
29.
Enomoto H, Heuckeroth RO, Golden JP, Johnson EM, Milbrandt J (2000) Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin. Development 127:4877–4889.
30.
Enomoto H, Hughes I, Golden J, Baloh RH, Yonemura S, Heuckeroth RO, Johnson EM Jr, Milbrandt J (2004) GFRalpha1 expression in cells lacking RET is dispensable for organogenesis and nerve regeneration. Neuron 44:623–636.
31.
Erickson JT, Brosenitsch TA, Katz DM (2001) Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor are required simultaneously for survival of dopaminergic primary sensory neurons in vivo. J Neurosci 21:581–589.
32.
Fundin BT, Mikaels A, Westphal H, Ernfors P (1999) A rapid and dynamic regulation of GDNF-family ligands and receptors correlate with the developmental dependency of cutaneous sensory innervation. Development 126:2597–2610.
33.
Garcia-Arraras JE, Rojas-Soto M, Jimenez LB, Diaz-Miranda L (2001) The enteric nervous system of echinoderms: unexpected complexity revealed by neurochemical analysis. J Exp Biol 204:865–873.
34.
Gaultier C, Amiel J, Dauger S, Trang H, Lyonnet S, Gallego J, Simonneau M (2004) Genetics and early disturbances of breathing control. Pediatr Res 55:729–733.
35.
Gaultier C, Trang H, Dauger S, Gallego J (2005) Pediatric disorders with autonomic dysfunction: what role for PHOX2B? Pediatr Res 58:1–6.
36.
Golden JP, DeMaro JA, Osborne PA, Milbrandt J, Johnson EM Jr (1999) Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Exp Neurol 158:504–528.
37.
Goodrich JT, Bernd P, Sherman D, Gershon MD (1980) Phylogeny of enteric serotonergic neurons. J Comp Neurol 190:15–28.
38.
Haase G, Dessaud E, Garces A, de Bovis B, Birling M, Filippi P, Schmalbruch H, Arber S, deLapeyriere O (2002) GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools. Neuron 35:893–905.
39.
Hahn M, Bishop J (2001) Expression pattern of Drosophila ret suggests a common ancestral origin between the metamorphosis precursors in insect endoderm and the vertebrate enteric neurons. Proc Natl Acad Sci USA 98:1053–1058.
40.
Hashino E, Johnson EM Jr, Milbrandt J, Shero M, Salvi RJ, Cohan CS (1999) Multiple actions of neurturin correlate with spatiotemporal patterns of Ret expression in developing chick cranial ganglion neurons. J Neurosci 19:8476–8486.
41.
Hashino E, Shero M, Junghans D, Rohrer H, Milbrandt J, Johnson EM Jr (2001) GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development. Development 128:3773–3782.
42.
Hätinen T, Holm L, Airaksinen MS (2006) Molecular evolution of GDNF family ligand – receptor pairs. Soc Neurosci Abstract (in press).
43.
Heathcote RD, Sargent PB (1987) Growth and morphogenesis of an autonomic ganglion. I. Matching neurons with target. J Neurosci 7:2493–2501.
44.
Heger A, Wilton CA, Sivakumar A, Holm L (2005) ADDA: a domain database with global coverage of the protein universe. Nucleic Acids Res 33:D188-D191.
45.
Heuckeroth RO, Enomoto H, Grider JR, Golden JP, Hanke JA Jackman A, Molliver DC, Bardgett ME, Snider WD, Johnson EM Jr, Milbrandt J (1999) Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron 22:253–263.
46.
Hiltunen PH, Airaksinen MS (2004) Sympathetic cholinergic target innervation requires GDNF family receptor GFRα2. Mol Cell Neurosci 26:450–457.
47.
Homma S, Oppenheim RW, Yaginuma H, Kimura S (2000) Expression pattern of GDNF, c-ret, and GFRalphas suggests novel roles for GDNF ligands during early organogenesis in the chick embryo. Dev Biol 217:121–137.
48.
Honma Y, Araki T, Gianino S, Bruce A, Heuckeroth R, Johnson EM Jr, Milbrandt J (2002) Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35:267–282.
49.
Kashuk CS, Stone EA, Grice EA, Portnoy ME, Green ED, Sidow A, Chakravarti A, McCallion AS (2005) Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence. Proc Natl Acad Sci USA 102:8949–8954.
50.
Katz DM (2005) Regulation of respiratory neuron development by neurotrophic and transcriptional signaling mechanisms. Respir Physiol Neurobiol 149:99–109.
51.
Kholodilov N, Yarygina O, Oo TF, Zhang H, Sulzer D, Dauer W, Burke RE (2004) Regulation of the development of mesencephalic dopaminergic systems by the selective expression of glial cell line-derived neurotrophic factor in their targets. J Neurosci 24:3136–3146.
52.
Kjaer S, Ibáñez CF (2003) Identification of a surface for binding to the GDNF/GFRα1 complex in the first cadherin-like domain of RET. J Biol Chem 278:47898–47904.
53.
Lang D, Epstein JA (2003) Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer. Hum Mol Genet 12:937–945.
54.
Leppänen VM, Bespalov MM, Runeberg-Roos P, Puurand U, Merits A, Saarma M, Goldman A (2004) The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation. EMBO J 23:1452–1462.
55.
Li Z, Wang B, Wu X, Cheng SY, Paraoan L, Zhou J (2005) Identification, expression and functional characterization of the GRAL gene. J Neurochem 95:361–376.
56.
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132.
57.
Lindahl M, Poteryaev D, Yu L, Arumäe U, Timmusk T, Bongarzone I, Aiello A, Pierotti MA, Airaksinen MS, Saarma M (2001) Human glial cell line-derived neurotrophic factor receptor α4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J Biol Chem 276:9344–9351.
58.
Lindahl M, Timmusk T, Rossi J, Saarma M, Airaksinen MS (2000) Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development. Mol Cell Neurosci 15:522–533.
59.
Lindfors PH, Voikar V, Rossi J, Airaksinen MS (2006a) Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in GDNF family receptor α2 knockout mice. J Neurosci 26:1953–1960.
60.
Lindfors PH, Lindahl M, Rossi J, Saarma M, Airaksinen MS (2006b) Ablation of persephin receptor GFRα4 impairs thyroid calcitonin production in young mice. Endocrinology 147:2237–2244.
61.
Loewi O (1921) İber humorale İbertragbarkeit der Herznervenwirkung. Pflügers Arch ges Physiol 198:239–242.
62.
Love S, Plaha P, Patel NK, Hotton GR, Brooks DJ, Gill SS (2005) Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med 11:703–704.
63.
Manié S, Santoro M, Fusco A, Billaud M (2001) The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17:580–589.
64.
Marcos-Gutierrez CV, Wilson SW, Holder N, Pachnis V (1997) The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis. Oncogene 14:879–889.
65.
McCallion AS, Stames E, Conlon RA, Chakravarti A (2003) Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb. Proc Natl Acad Sci USA 100:1826–1831.
66.
Meng X, Lindahl M, Hyvönen ME, Parvinen M, de Rooij DG, Hess MW, Raatikainen-Ahokas A, Sainio K, Rauvala H, Lakso M, Pichel JG, Westphal H, Saarma M, Sariola H (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287:1489–1493.
67.
Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, Rosenthal A (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382:76–79.
68.
Nishino J, Mochida K, Ohfuji Y, Shimazaki T, Meno C, Ohishi S, Matsuda Y, Fujii H, Saijoh Y, Hamada H (1999) GFRα3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron 23:725–736.
69.
Oppenheim RW, Houenou LJ, Parsadanian AS, Prevette D, Snider WD, Shen L (2000) Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: regulation of programmed cell death among motoneuron subtypes. J Neurosci 20:5001–5011.
70.
Pachnis V, Mankoo B, Costantini F (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119:1005–1017.
71.
Parichy DM, Mellgren EM, Rawls JF, Lopes SS, Kelsh RN, Johnson SL (2000) Mutational analysis of endothelin receptor b1 (rose) during neural crest and pigment pattern development in the zebrafish Danio rerio. Dev Biol 227:294–306.
72.
Parisi MA, Kapur RP (2000) Genetics of Hirschsprung disease. Curr Opin Pediatr 12:610–617.
73.
Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 399:366–370.
74.
Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76.
75.
Pozas E, Ibáñez CF (2005) GDNF and GFRalpha1 promote differentiation and tangential migration of cortical GABAergic neurons. Neuron 45:701–713.
76.
Read RD, Goodfellow PJ, Mardis ER, Novak N, Armstrong JR, Cagan RL (2005) A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171:1057–1081.
77.
Robertson K, Mason I (1995) Expression of ret in the chicken embryo suggests roles in regionalisation of the vagal neural tube and somites and in development of multiple neural crest and placodal lineages. Mech Dev 53:329–344.
78.
Rossi J, Luukko K, Poteryaev D, Laurikainen A, Sun Y-F, Laakso T, Tuominen R, Lakso M, Rauvala H, Arumäe U, Pasternack M, Saarma M, Airaksinen MS (1999) Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFRα2, a functional neurturin receptor. Neuron 22:243–252.
79.
Rossi J, Tomac A, Saarma M, Airaksinen MS (2000) Distinct roles for GFRα1 and GFRα2 signalling in different cranial parasympathetic ganglia in vivo. Eur J Neurosci 12:3944–3952.
80.
Ruaro ME, Stebel M, Vatta P, Marzinotto S, Schneider C (2000) Analysis of the domain requirement in Gas1 growth suppressing activity. FEBS Lett 481:159–163.
81.
Sánchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73.
82.
Sariola H, Saarma M (2003) Novel functions and signalling pathways for GDNF. J Cell Sci 116:3855–3862.
83.
Schuchardt A, D’Agati V, Larsson-Blomberg L, Costantini F, Pachnis V (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383.
84.
Schuchardt A, Srinivas S, Pachnis V, Costantini F (1995) Isolation and characterization of a chicken homolog of the c-ret proto-oncogene. Oncogene 10:641–649.
85.
Schueler-Furman O, Glick E, Segovia J, Linial M (2006) Is GAS1 a co-receptor for the GDNF family of ligands? Trends Pharmacol Sci 27:72–77.
86.
Shepherd IT, Beattie CE, Raible DW (2001) Functional analysis of zebrafish GDNF. Dev Biol 231:420–435.
87.
Shepherd IT, Pietsch J, Elworthy S, Kelsh RN, Raible DW (2004) Roles for GFRalpha1 receptors in zebrafish enteric nervous system development. Development 131:241–249.
88.
Soler RM, Dolcet X, Encinas M, Egea J, Bayascas JR, Comella JX (1999) Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons. J Neurosci 19:9160–9169.
89.
Sugaya R, Ishimaru S, Hosoya T, Saigo K, Emori Y (1994) A Drosophila homolog of human proto-oncogene ret transiently expressed in embryonic neuronal precursor cells including neuroblasts and CNS cells. Mech Dev 45:139–145.
90.
Takahashi M (2001) The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 12:361–373.
91.
Taraviras S, Marcos-Gutierrez CV, Durbec P, Jani H, Grigoriou M, Sukumaran M, Wang LC, Hynes M, Raisman G, Pachnis V (1999) Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. Development 126:2785–2797.
92.
Taylor EW, Jordan D, Coote JH (1999) Central control of the cardiovascular and respiratory systems and their interactions in vertebrates. Physiol Rev 79:855–916.
93.
Thompson J, Doxakis E, Pinon LGP, Strachan P, Buj-Bello A, Wyatt S, Buchman VL, Davies AM (1998) GFRα-4, a new GDNF family receptor. Mol Cell Neurosci 11:117–126.
94.
Whitehead J, Keller-Peck C, Kucera J, Tourtellotte WG (2005) Glial cell-line derived neurotrophic factor-dependent fusimotor neuron survival during development. Mech Dev 122:27–41.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.