Renal agenesis and the absence of enteric neurons in mice lacking GDNF.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.
Sánchez
M P
MP
Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Silos-Santiago
I
I
Frisén
J
J
He
B
B
Lira
S A
SA
Barbacid
M
M
D000818:Animals; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004064:Digestive System / Q000196:embryology* / Q000294:innervation; D004065:Digestive System Abnormalities; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007668:Kidney / Q000002:abnormalities / Q000196:embryology*; D051379:Mice; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
D029721:Drosophila Proteins; C495040:Gdnf 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; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D004298:Dopamine