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@ARTICLE{Zhang:138219,
      author       = {Zhang, Jingzhong and Götz, Sebastian and Vogt-Weisenhorn,
                      Daniela and Simeone, Antonio and Wurst, Wolfgang and
                      Prakash, Nilima},
      title        = {{A} {WNT}1-regulated developmental gene cascade prevents
                      dopaminergic neurodegeneration in adult {E}n1(+/-) mice.},
      journal      = {Neurobiology of disease},
      volume       = {82},
      issn         = {0969-9961},
      address      = {Orlando, Fla.},
      publisher    = {Academic Press},
      reportid     = {DZNE-2020-04541},
      pages        = {32-45},
      year         = {2015},
      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.},
      keywords     = {Adaptor Proteins, Signal Transducing / Animals /
                      Brain-Derived Neurotrophic Factor: genetics / Brain-Derived
                      Neurotrophic Factor: metabolism / Cell Differentiation:
                      genetics / Dopaminergic Neurons: metabolism / Dopaminergic
                      Neurons: pathology / Gene Expression Regulation,
                      Developmental / Homeodomain Proteins: genetics /
                      Intercellular Signaling Peptides and Proteins: genetics /
                      Intercellular Signaling Peptides and Proteins: metabolism /
                      Mice / Mice, Transgenic / Nerve Degeneration: genetics /
                      Nerve Degeneration: metabolism / Nerve Degeneration:
                      pathology / Parkinson Disease: metabolism / Parkinson
                      Disease: pathology / Signal Transduction: genetics /
                      Substantia Nigra: metabolism / Substantia Nigra: pathology /
                      Up-Regulation / Ventral Tegmental Area: metabolism / Ventral
                      Tegmental Area: pathology / Wnt1 Protein: metabolism /
                      Brain-Derived Neurotrophic Factor (NLM Chemicals) / Dkk3
                      protein, mouse (NLM Chemicals) / En1 protein, mouse (NLM
                      Chemicals) / Homeodomain Proteins (NLM Chemicals) /
                      Intercellular Signaling Peptides and Proteins (NLM
                      Chemicals) / Wnt1 Protein (NLM Chemicals)},
      cin          = {Ext HZM / AG Wurst},
      ddc          = {570},
      cid          = {I:(DE-2719)5000050 / I:(DE-2719)1140001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26049140},
      doi          = {10.1016/j.nbd.2015.05.015},
      url          = {https://pub.dzne.de/record/138219},
}