GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney.
Glial cell line-derived neurotrophic factor (GDNF) is a distant member of the TGFbeta protein family that is essential for neuronal survival and renal morphogenesis. We show that mice who are deficient in the glycosyl-phosphatidyl inositol (GPI) -linked protein GFRalpha1 (GDNFRalpha) display deficits in the kidneys, the enteric nervous system, and spinal motor and sensory neurons that are strikingly similar to those of the GDNF- and Ret-deficient mice. GFRalpha1-deficient dopaminergic and nodose sensory ganglia neurons no longer respond to GDNF or to the structurally related protein neurturin (NTN) but can be rescued when exposed to GDNF or neurturin in the presence of soluble GFRalpha1. In contrast, GFRalpha1-deficient submandibular parasympathetic neurons retain normal response to these two factors. Taken together with the available genetic and biochemical data, these findings support the idea that GFRalpha1 and the transmembrane tyrosine kinase Ret are both necessary receptor components for GDNF in the developing kidney and nervous system, and that GDNF and neurturin can mediate some of their activities through a second receptor.
Cacalano
G
G
Department of Molecular Biology, Genentech, Incorporated, South San Francisco, California 94080, USA.
Fariñas
I
I
Wang
L C
LC
Hagler
K
K
Forgie
A
A
Moore
M
M
Armanini
M
M
Phillips
H
H
Ryan
A M
AM
Reichardt
L F
LF
Hynes
M
M
Davies
A
A
Rosenthal
A
A
D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins; D005314:Embryonic and Fetal Development / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007422:Intestines / Q000294:innervation; D007668:Kidney / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology* / Q000254:growth & development / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051101:Neurturin; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology*
D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495056:Nrtn protein, mouse; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse