Broad specificity of GDNF family receptors GFRα1 and GFRα2 for GDNF and NTN in neurons and transfected cells

The glial cell line‐derived neurotrophic factor (GDNF) family of ligands binds to lipid anchored proteins termed GDNF family receptor (GFR)αs, and then activates the RET receptor tyrosine kinase, by ligand GFRα. The binding of soluble GFRαs to transfected cells suggested that different GFRαs were dedicated to particular ligands, with GDNF acting primarily or entirely through GFRα1, and neurturin (NTN), through GFRα2. More recent evidence has suggested the possibility of cross‐talk between these ligands and the two receptors. We examined here whether crosstalk between the GDNF ligands and the GFRαs is biologically relevant, using midbrain dopaminergic, and parasympathetic, submandibular gland neurons. By biochemical and genetic addition and/or deletion of GFRα1 and 2, we show that in both neuronal cell types, robust biological activities of GDNF or NTN can be mediated by either GFRα1 or GFRα2, although GDNF is slightly more potent in dopaminergic (DA) neurons which normally express GFRα1, and NTN in submandibular neurons which normally express GFRα2. Throughout the body, GDNF and NTN are likely to have important biological actions on both GFRα1‐ and GFRα2‐expressing cells. J. Neurosci. Res. 61:1–9, 2000. © 2000 Wiley‐Liss, Inc.

[1]  J. Milbrandt,et al.  Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  N. Belluardo,et al.  Multiple GPI-Anchored Receptors Control GDNF-Dependent and Independent Activation of the c-Ret Receptor Tyrosine Kinase , 1998, Molecular and Cellular Neuroscience.

[3]  Barbara Moffat,et al.  A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor , 1997, Nature.

[4]  P. Bonaventure,et al.  Molecular cloning, expression and tissue distribution of glial-cell-line-derived neurotrophic factor family receptor alpha-3 (GFRalpha-3). , 1998, European journal of biochemistry.

[5]  C. Henderson,et al.  GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. , 1994, Science.

[6]  J. Lile,et al.  GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. , 1993, Science.

[7]  J. Milbrandt,et al.  Artemin, a Novel Member of the GDNF Ligand Family, Supports Peripheral and Central Neurons and Signals through the GFRα3–RET Receptor Complex , 1998, Neuron.

[8]  A. Whitty,et al.  Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Davies,et al.  GDNF is an age-specific survival factor for sensory and autonomic neurons , 1995, Neuron.

[10]  H. Phillips,et al.  TGFβ2 and TGFβ3 are potent survival factors for midbrain dopaminergic neurons , 1994, Neuron.

[11]  H. Phillips,et al.  Neurotrophic‐4/5 is a survival factor for embryonic midbrain dopaminergic neurons in enriched cultures , 1994 .

[12]  L. Olson,et al.  Glial cell line‐derived neurotrophic factor stimulates fiber formation and survival in cultured neurons from peripheral autonomic ganglia , 1995, Journal of neuroscience research.

[13]  J. Milbrandt,et al.  Neurturin, a relative of glial-cell-line-derived neurotrophic factor , 1996, Nature.

[14]  A. Rosenthal,et al.  The GDNF Protein FamilyGene Ablation Studies Reveal What They Really Do and How , 1999, Neuron.

[15]  A. Buj-Bello,et al.  GFRα-4, a New GDNF Family Receptor , 1998, Molecular and Cellular Neuroscience.

[16]  Jonas Frisén,et al.  Renal agenesis and the absence of enteric neurons in mice lacking GDNF , 1996, Nature.

[17]  C. Worby,et al.  Identification and Characterization of GFRα-3, a Novel Co-receptor Belonging to the Glial Cell Line-derived Neurotrophic Receptor Family* , 1998, The Journal of Biological Chemistry.

[18]  Mart Saarma,et al.  Defects in enteric innervation and kidney development in mice lacking GDNF , 1996, Nature.

[19]  E. Arenas,et al.  Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons , 1995, The Journal of cell biology.

[20]  M. Tessier-Lavigne,et al.  Control of neuronal diversity by the floor plate: Contact-mediated induction of midbrain dopaminergic neurons , 1995, Cell.

[21]  J. Milbrandt,et al.  Neurturin Exerts Potent Actions on Survival and Function of Midbrain Dopaminergic Neurons , 1998, The Journal of Neuroscience.

[22]  J. Milbrandt,et al.  Gene Targeting Reveals a Critical Role for Neurturin in the Development and Maintenance of Enteric, Sensory, and Parasympathetic Neurons , 1999, Neuron.

[23]  A. Buj-Bello,et al.  Characterization of a multicomponent receptor for GDNF , 1996, Nature.

[24]  I. Fariñas,et al.  GFRα1 Is an Essential Receptor Component for GDNF in the Developing Nervous System and Kidney , 1998, Neuron.

[25]  G. Raisman,et al.  Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. , 1999, Development.

[26]  J. Milbrandt,et al.  GFRα1-Deficient Mice Have Deficits in the Enteric Nervous System and Kidneys , 1998, Neuron.

[27]  R. Vejsada,et al.  Persephin, a Novel Neurotrophic Factor Related to GDNF and Neurturin , 1998, Neuron.

[28]  J. Milbrandt,et al.  TrnR2, a Novel Receptor That Mediates Neurturin and GDNF Signaling through Ret , 1997, Neuron.

[29]  Jimi Adu,et al.  Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase , 1997, Nature.

[30]  M. Saarma,et al.  Retarded Growth and Deficits in the Enteric and Parasympathetic Nervous System in Mice Lacking GFRα2, a Functional Neurturin Receptor , 1999, Neuron.

[31]  J. Louis,et al.  GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF , 1996, Cell.

[32]  I. Fariñas,et al.  Renal and neuronal abnormalities in mice lacking GDNF , 1996, Nature.

[33]  T. Boone,et al.  GFRα-2 and GFRα-3 Are Two New Receptors for Ligands of the GDNF Family , 1997, The Journal of Biological Chemistry.

[34]  Marc Tessier-Lavigne,et al.  Induction of midbrain dopaminergic neurons by Sonic hedgehog , 1995, Neuron.