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The Journal of Neuroscience, May 1, 2000, 20(9):3182-3190
Glial Cell Line-Derived Neurotrophic Factor Is Essential for
Postnatal Survival of Midbrain Dopamine Neurons
Ann-Charlotte
Granholm1, 2, 3,
Mary
Reyland1,
David
Albeck1, 3,
Linda
Sanders1, 3,
Greg
Gerhardt2, 3,
George
Hoernig1,
Liya
Shen4,
Heiner
Westphal4, and
Barry
Hoffer5
Departments of 1 Basic Science and
2 Pharmacology and 3 The Neuroscience Training
Program, University of Colorado Health Sciences Center, Denver,
Colorado 80262, 4 National Institute of Child Health and
Human Development, LMGD, National Institutes of Health,
Bethesda, Maryland 20892, and 5 Intramural Research
Program, National Institute of Drug Abuse, Baltimore, Maryland
21224
Glial cell line-derived neurotrophic factor (GDNF) is one of the
most potent trophic factors that have been identified for midbrain
dopamine (DA) neurons. Null mutations for trophic factor genes
have been used frequently for studies of the role of these important
proteins in brain development. One problem with these studies has been
that often only prenatal development can be studied because many of the
knockout strains, such as those with GDNF null mutations, will die
shortly after birth. In this study, we looked at the continued fate of
specific neuronal phenotypes from trophic factor knockout mice beyond
the time that these animals die. By transplanting fetal neural
tissues from GDNF  /, GDNF +/, and wild-type (WT) mice into the
brain of adult wild-type mice, we demonstrate that the continued
postnatal development of ventral midbrain dopamine neurons is severely
disturbed as a result of the GDNF null mutation. Ventral midbrain
grafts from / fetuses have markedly reduced DA neuron numbers and
fiber outgrowth. Moreover, DA neurons in such transplants can be
"rescued" by immersion in GDNF before grafting. These findings
suggest that postnatal survival and/or phenotypic expression of ventral
mesencephalic DA neurons is dependent on GDNF. In addition, we present
here a strategy for studies of maturation and even aging of tissues from trophic factor and other knockout animals that do not survive past birth.
Key words:
trophic factors; GDNF; neurodegeneration; transplantation; neural development; substantia nigra; DA neurons
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093182-09$05.00/0
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