TY  - JOUR
AU  - Zhang, Jingzhong
AU  - Götz, Sebastian
AU  - Vogt-Weisenhorn, Daniela
AU  - Simeone, Antonio
AU  - Wurst, Wolfgang
AU  - Prakash, Nilima
TI  - A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1(+/-) mice.
JO  - Neurobiology of disease
VL  - 82
SN  - 0969-9961
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2020-04541
SP  - 32-45
PY  - 2015
AB  - 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.
KW  - Adaptor Proteins, Signal Transducing
KW  - Animals
KW  - Brain-Derived Neurotrophic Factor: genetics
KW  - Brain-Derived Neurotrophic Factor: metabolism
KW  - Cell Differentiation: genetics
KW  - Dopaminergic Neurons: metabolism
KW  - Dopaminergic Neurons: pathology
KW  - Gene Expression Regulation, Developmental
KW  - Homeodomain Proteins: genetics
KW  - Intercellular Signaling Peptides and Proteins: genetics
KW  - Intercellular Signaling Peptides and Proteins: metabolism
KW  - Mice
KW  - Mice, Transgenic
KW  - Nerve Degeneration: genetics
KW  - Nerve Degeneration: metabolism
KW  - Nerve Degeneration: pathology
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Signal Transduction: genetics
KW  - Substantia Nigra: metabolism
KW  - Substantia Nigra: pathology
KW  - Up-Regulation
KW  - Ventral Tegmental Area: metabolism
KW  - Ventral Tegmental Area: pathology
KW  - Wnt1 Protein: metabolism
KW  - Brain-Derived Neurotrophic Factor (NLM Chemicals)
KW  - Dkk3 protein, mouse (NLM Chemicals)
KW  - En1 protein, mouse (NLM Chemicals)
KW  - Homeodomain Proteins (NLM Chemicals)
KW  - Intercellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - Wnt1 Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26049140
DO  - DOI:10.1016/j.nbd.2015.05.015
UR  - https://pub.dzne.de/record/138219
ER  -