Marked dopaminergic cell loss subsequent to developmental, intranigral expression of glial cell line-derived neurotrophic factor.
Glial cell line-derived neurotrophic factor (GDNF) shows potent neuroprotective as well as neurorestorative actions on the adult neurons impacted in animal models of Parkinson's disease (PD). Long-term pharmaco-physiological effects of GDNF on developing dopaminergic (DA) neurons have not yet been explored because of technical difficulties in producing prolonged cell type-specific delivery of this neurotrophic factor in mammalian embryonic brain. The current studies used our previously characterized 9.0-kb tyrosine hydroxylase promoter to produce transgenic mice with neuronal cell type-specific expression of GDNF in substantia nigra pars compacta (SNc) and locus coeruleus (LC). These mice were used to test the parsimonious hypothesis that increased developmental expression of GDNF in SNc and LC would significantly enhance the number of postmitotic adult neurons. To our surprise, adult transgenic mice carrying the TH9.0kb-GDNF hybrid gene showed dramatic reductions in both the numbers and the volumes of SNc-DA and LC-noradrenergic (NA) neurons by quantitative morphometric analysis. The decrease in the number of DA neurons was apparent as early as postnatal day 2, the period before the major naturally occurring apoptotic cell death in midbrain. Aged transgenic mice exhibited no further significant deficits in motor behaviors. These data suggest that continuous, early developmental GDNF expression exerts physiological effects on newly differentiated, immature dopamine neurons that differ from those observed on more mature and adult DA neurons. Further elucidation of the mechanisms underlying differential GDNF actions will greatly improve the pharmacological efficacy of GDNF in fetal neural transplantation as well as adult neuronal gene therapy in PD patients.
Chun
Hong S
HS
Department of Neurology and Neuroscience, Weill Medical College of Cornell University at the W. M. Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
Yoo
Myung S
MS
DeGiorgio
Lorraine A
LA
Volpe
Bruce T
BT
Peng
Diana
D
Baker
Harriet
H
Peng
Chu
C
Son
Jin H
JH
D000375:Aging / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D048429:Cell Size / Q000187:drug effects / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine