Absolute requirement of GDNF for adult catecholaminergic neuron survival.
GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain.
Alberto
A
Pascual
María
M
Hidalgo-Figueroa
José I
JI
Piruat
C Oscar
CO
Pintado
Raquel
R
Gómez-Díaz
José
J
López-Barneo
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D002395:Catecholamines / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018476:Hypokinesia / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D002395:Catecholamines; D051100:Glial Cell Line-Derived Neurotrophic Factor; D013629:Tamoxifen; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D010751:Phosphopyruvate Hydratase