title: A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1(+/-) mice.
abstract: The protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygous for the homeodomain transcription factor Engrailed 1 (En1(+/-) mice). Neurotoxin-based animal models of PD, in contrast, are characterized by the fast and partly reversible degeneration of the SNc and VTA DA neurons. The secreted protein WNT1 was previously shown to be strongly induced in the neurotoxin-injured adult ventral midbrain (VM), and to protect the SNc and VTA DA neurons from cell death in this context. We demonstrate here that the sustained and ectopic expression of Wnt1 in the SNc and VTA DA neurons of En1(+/Wnt1) mice also protected these genetically affected En1 heterozygote (En1(+/-)) neurons from their premature degeneration in the adult mouse VM. We identified a developmental gene cascade that is up-regulated in the adult En1(+/Wnt1) VM, including the direct WNT1/β-catenin signaling targets Lef1, Lmx1a, Fgf20 and Dkk3, as well as the indirect targets Pitx3 (activated by LMX1A) and Bdnf (activated by PITX3). We also show that the secreted neurotrophin BDNF and the secreted WNT modulator DKK3, but not the secreted growth factor FGF20, increased the survival of En1 mutant dopaminergic neurons in vitro. The WNT1-mediated signaling pathway and its downstream targets BDNF and DKK3 might thus provide a useful means to treat certain genetic and environmental (neurotoxic) forms of human PD.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. Electronic address: Jingzhong.Zhang@mdc-berlin.de.
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. Electronic address: sebastian.goetz@helmholtz-muenchen.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Götz
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany; Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Standort München, Schillerstr. 44, D-80336 München, Germany. Electronic address: daniela.vogt@helmholtz-muenchen.de.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Vogt Weisenhorn
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso", I-80131 Naples, Italy; IRCCS Neuromed, I-86077 Pozzilli, IS, Italy. Electronic address: antonio.simeone@igb.cnr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany; Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Standort München, Schillerstr. 44, D-80336 München, Germany; Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstrasse 44, D-80336 München, Germany. Electronic address: wurst@helmholtz-muenchen.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany; Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. Electronic address: nilima.prakash@hshl.de.
authors.forename: Nilima
authors.initials: N
authors.lastname: Prakash
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000473:pathology; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; C405061:Dkk3 protein, mouse; C080330:En1 protein, mouse; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051155:Wnt1 Protein
keywords: Bdnf; Dkk3; Dopamine neuron; Fgf20; Lef1; Lmx1a; Neuroprotection; Parkinson's Disease; Pitx3; Survival