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The Journal of Neuroscience, July 1, 1998, 18(13):4929-4937
Neurturin Exerts Potent Actions on Survival and Function of
Midbrain Dopaminergic Neurons
Brian A.
Horger1,
Merry
C.
Nishimura1,
Mark P.
Armanini1,
Li-Chong
Wang1,
Kris T.
Poulsen1,
Carl
Rosenblad6,
Deniz
Kirik6,
Barbara
Moffat2,
Laura
Simmons3,
Eugene
Johnson Jr5,
Jeff
Milbrandt4,
Arnon
Rosenthal1,
Anders
Bjorklund6,
Richard A.
Vandlen2,
Mary A.
Hynes1, and
Heidi S.
Phillips1
Departments of 1 Neuroscience,
2 Protein Chemistry, and
3 Molecular Biology, Genentech, South San
Francisco, California 94080, Departments of
4 Pathology and
5 Pharmacology, Washington University Medical
School, St. Louis, Missouri 63110, and
6 Wallenberg Neurocentrum Institute, Lund, Sweden
Glial cell line-derived neurotrophic factor (GDNF) exhibits potent
effects on survival and function of midbrain dopaminergic (DA) neurons
in a variety of models. Although other growth factors expressed in the
vicinity of developing DA neurons have been reported to support
survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent
effects on survival and function of midbrain DA neurons. Our findings
indicate that NTN mRNA is sequentially expressed in the ventral
midbrain and striatum during development and that NTN exhibits
survival-promoting actions on both developing and mature DA neurons.
In vitro, NTN supports survival of embryonic DA neurons,
and in vivo, direct injection of NTN into the substantia nigra protects mature DA neurons from cell death induced by 6-OHDA. Furthermore, administration of NTN into the striatum of intact adult
animals induces behavioral and biochemical changes associated with
functional upregulation of nigral DA neurons. The similarity in potency
and efficacy of NTN and GDNF on DA neurons in several paradigms stands
in contrast to the differential distribution of the receptor components
GDNF Family Receptor  1 (GFR1) and GFR2 within the ventral
mesencephalon. These results suggest that NTN is an endogenous trophic
factor for midbrain DA neurons and point to the possibility that GDNF
and NTN may exert redundant trophic influences on nigral DA neurons
acting via a receptor complex that includes GFR1.
Key words:
neurturin; GDNF; dopaminergic; trophic; Parkinson's; nigrostriatal; 6-OHDA
Copyright © 1998 Society for Neuroscience 0270-6474/98/18134929-09$05.00/0
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