GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys.
Glial cell line-derived neurotrophic factor (GDNF) signals through a receptor complex composed of the Ret tyrosine kinase and a glycosylphosphatidylinositol- (GPI-) anchored cell surface coreceptor, either GDNF family receptor alpha1 (GFR alpha1) or GFR alpha2. To investigate the usage of these coreceptors for GDNF signaling in vivo, gene targeting was used to produce mice lacking the GFR alpha1 coreceptor. GFR alpha1-deficient mice demonstrate absence of enteric neurons and agenesis of the kidney, characteristics that are reminiscent of both GDNF- and Ret-deficient mice. Midbrain dopaminergic and motor neurons in GFR alpha1 null mice were normal. Minimal or no neuronal losses were observed in a number of peripheral ganglia examined, including the superior cervical and nodose, which are severely affected in both Ret- and GDNF-deficient mice. These results suggest that while stringent physiologic pairing exists between GFR alpha1 and GDNF in renal and enteric nervous system development, significant cross-talk between GDNF and other GFR alpha coreceptors must occur in other neuronal populations.
Enomoto
H
H
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Araki
T
T
Jackman
A
A
Heuckeroth
R O
RO
Snider
W D
WD
Johnson
E M
EM
Milbrandt
J
J
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000002:abnormalities / Q000503:physiopathology*; D005260:Female; D018390:Gene Targeting; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007668:Kidney / Q000002:abnormalities / Q000503:physiopathology*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics
D029721:Drosophila Proteins; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse