Ac. Granholm et al., Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons, J NEUROSC, 20(9), 2000, pp. 3182-3190
Glial cell line-derived neurotrophic factor (GDNF) is one of the most poten
t trophic factors that have been identified for midbrain dopamine (DA) neur
ons. Null mutations for trophic factor genes have been used frequently for
studies of the role of these important proteins in brain development. One p
roblem with these studies has been that often only prenatal development can
be studied because many of the knockout strains, such as those with GDNF n
ull mutations, will die shortly after birth. In this study, we looked at th
e continued fate of specific neuronal phenotypes from trophic factor knocko
ut mice beyond the time that these animals die. By transplanting fetal neur
al tissues from GDNF -/-, GDNF +/-, and wild-type (WT) mice into the brain
of adult wild-type mice, we demonstrate that the continued postnatal develo
pment of ventral midbrain dopamine neurons is severely disturbed as a resul
t of the GDNF null mutation. Ventral midbrain grafts from -/- fetuses have
markedly reduced DA neuron numbers and fiber outgrowth. Moreover, DA neuron
s in such transplants can be "rescued" by immersion in GDNF before grafting
. These findings suggest that postnatal survival and/or phenotypic expressi
on of ventral mesencephalic DA neurons is dependent on GDNF. In addition, w
e present here a strategy for studies of maturation and even aging of tissu
es from trophic factor and other knockout animals that do not survive past
birth.