A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1(+/-) mice.
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.
['Zhang|Jingzhong|J|', 'Götz|Sebastian|S|', 'Vogt Weisenhorn|Daniela M|DM|', 'Simeone|Antonio|A|', 'Wurst|Wolfgang|W|', 'Prakash|Nilima|N|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D019208:Brain-Derived Neurotrophic Factor D002454:Cell Differentiation D059290:Dopaminergic Neurons D018507:Gene Expression Regulation, Developmental D018398:Homeodomain Proteins D036341:Intercellular Signaling Peptides and Proteins D051379:Mice D008822:Mice, Transgenic D009410:Nerve Degeneration D010300:Parkinson Disease D015398:Signal Transduction D013378:Substantia Nigra D015854:Up-Regulation D017557:Ventral Tegmental Area D051155:Wnt1 Protein
Parkinson's Disease Lef1 Lmx1a Fgf20 Dkk3 Pitx3 Bdnf Survival Dopamine neuron Neuroprotection