title: Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons.
abstract: 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 alpha1 (GFRalpha1) and GFRalpha2 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 GFRalpha1.
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Horger
authors.forename: M C
authors.initials: MC
authors.lastname: Nishimura
authors.forename: M P
authors.initials: MP
authors.lastname: Armanini
authors.forename: L C
authors.initials: LC
authors.lastname: Wang
authors.forename: K T
authors.initials: KT
authors.lastname: Poulsen
authors.forename: C
authors.initials: C
authors.lastname: Rosenblad
authors.forename: D
authors.initials: D
authors.lastname: Kirik
authors.forename: B
authors.initials: B
authors.lastname: Moffat
authors.forename: L
authors.initials: L
authors.lastname: Simmons
authors.forename: E
authors.initials: E
authors.lastname: Johnson
authors.forename: J
authors.initials: J
authors.lastname: Milbrandt
authors.forename: A
authors.initials: A
authors.lastname: Rosenthal
authors.forename: A
authors.initials: A
authors.lastname: Bjorklund
authors.forename: R A
authors.initials: RA
authors.lastname: Vandlen
authors.forename: M A
authors.initials: MA
authors.lastname: Hynes
authors.forename: H S
authors.initials: HS
authors.lastname: Phillips
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000196:embryology; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051101:Neurturin; D009714:Nucleus Accumbens / Q000166:cytology / Q000196:embryology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000188:drug therapy / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000166:cytology* / Q000196:embryology; D013565:Sympatholytics
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D051101:Neurturin; C495056:Nrtn protein, mouse; D012333:RNA, Messenger; D013565:Sympatholytics; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D004298:Dopamine