A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1 mice

Zhang, Jingzhong; Götz, Sebastian; Weisenhorn, Daniela M. Vogt; Simeone, Antonio; Wurst, Wolfgang; Prakash, Nilima

doi:10.1016/j.nbd.2015.05.015

Cited by 34 publications

(46 citation statements)

References 64 publications

(115 reference statements)

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“…The latter effect is most likely a result of the reactivation of a gene cascade that is active during development (Zhang et al . ). A neuroprotective role of the Wnt1 pathway is at first glance counterintuitive given that this ligand is not expressed in the adult mesencephalon.…”

Section: Diversity Of Neurons In the Ventral Mesencephalic Dopaminergmentioning

confidence: 97%

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Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

Weisenhorn

Giesert

Wurst

2016

Journal of Neurochemistry

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Dopaminergic neurons in the ventral mesencephalon (the ventral mesencephalic dopaminergic complex) are known for their role in a multitude of behaviors, including cognition, reward, addiction and voluntary movement. Dysfunctions of these neurons are the underlying cause of various neuropsychiatric disorders, such as depression, addiction and schizophrenia. In addition, Parkinson's disease (PD), which is the second most common degenerative disease in developed countries, is characterized by the degeneration of dopaminergic neurons, leading to the core motor symptoms of the disease. However, only a subset of dopaminergic neurons in the ventral mesencephalon is highly vulnerable to the disease process. Indeed, research over several decades revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group with respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in different diseases. Here, we review how the concept of dopaminergic neuron diversity, assisted by the advent and application of new technologies, evolved and was refined over time and how it shaped our understanding of PD pathogenesis. Understanding this diversity of neurons in the ventral mesencephalic dopaminergic complex at all levels is imperative for the development of new and more selective drugs for both PD and various other neuropsychiatric diseases.

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Section: Diversity Of Neurons In the Ventral Mesencephalic Dopaminergmentioning

confidence: 97%

“…Thus, it is possible that one role of these genes in dopaminergic neurons is to protect the respective subpopulation upon injury by reactivating developmental programs (Zhang et al . ).…”

Section: Diversity Of Neurons In the Ventral Mesencephalic Dopaminergmentioning

confidence: 97%

Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

Weisenhorn

Giesert

Wurst

2016

Journal of Neurochemistry

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“…NSC grafts did not change the mRNA levels for a number of growth and neurotrophic factors, including glial cell‐derived growth factor ( Gdnf ) , insulin‐like growth factor 1 ( Igf1 ) , nerve growth factor ( Ngf ) , transforming growth factor α ( Tgfa ) , Tgfb and Fgf8 . By contrast, several DAergic‐specific developmental factors including En1/En2 , and the direct WβC‐signalling targets, Lef1 , LIM Hhomeobox transcription factor 1 α ( Lmx1a) and Fgf20, as well as the indirect Wnt1/β‐catenin targets pituitary homeobox 3 ( Pitx3 ) and brain‐derived neurotrophic factor ( Bdnf ) (see Zhang et al, , and references therein), were up‐regulated of about 2.5–3.5‐fold in MPTP + NSC grafts versus MPTP + PBS sham controls, with Wnt1 being the most up‐regulated DAergic‐specific neurodevelopmental and pro‐survival factor amongst those studied (L'Episcopo, Tirolo, Serapide, et al, ). Likewise, looking at 19 WβC‐signalling members, the canonical Wnts components were sharply down‐regulated in the aged MPTP brain, whereas major Wnt‐antagonists, including the Dkk and sFrp families of Wnt inhibitors, and Gsk3b showed marked up‐regulation of 6‐to‐14‐fold in aged‐MPTP tissues.…”

Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

“…As recalled in previous sections, both earlier and more recent reports indicate that GSK‐3β inhibitors can promote adult neurogenesis both under normal and injury conditions, either in vivo or in vitro. In vitro protocols that modulate Wnt signalling to improve cell therapies for PD are increasingly being developed (Arenas, ; Broski et al, ; Joksimovic & Awatrami, ; Kirkeby et al, , ; Kriks et al, ; Parish & Thompson, ; Prakash & Wurst, 2014; Toledo et al, ; Zhang et al, ). To date, a number of GSK‐3β‐antagonists have been described, some of which have been tested for their potential to promote adult neurogenesis (Table ).…”

Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

“…The chief role of Wnts during DAergic neuron development is underscored by the specific requirement of a Wnt1-induced genetic cascade for the establishment of progenitor cells and DAergic terminal differentiation in the later stages of embryogenesis (see Arenas, 2014;Brodski et al, 2019;Joksimovic & Awatramani, 2014;Prakash & Wurst, 2006;Prakash & Wurst, 2014;Zhang et al, 2015). Hence, canonical Wnt signalling is critical for midbrain DAergic progenitor specification, proliferation, and neurogenesis.…”

Section: Ac Tivator S and Inhib Itor S Of The " Wnt-sig Nalosome " mentioning

confidence: 99%

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Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

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XQ‐1H attenuates ischemic injury in PC12 cells via Wnt/β‐catenin signaling though inhibition of apoptosis and promotion of proliferation

Hou

et al. 2020

Cell Biology International

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10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) is a new derivative of ginkgolide B and has previously been proven to exert neuroprotective effects on ischemic injury. However, it is not clear whether XQ-1H affects the cell survival and proliferation in oxygen-glucose deprivation/reoxygenation (OGD/R) damaged PC12 cells. Our results showed that OGD/R improved cell viability after 24 hr of posttreatment with XQ-1H (10 or 5 μM), inhibiting cell injury and apoptosis by upregulating the expression of brain-derived neurotrophic factor, nerve growth factor, and antiapoptotic B-cell lymphoma-extra large, while reducing proapoptotic cleaved caspase-3 protein. By introducing the Wnt/β-catenin signaling inhibitor XAV-939 and 5-bromo-2′-deoxyuridine staining, it was proved that XQ-1H promoted the proliferation of PC12 cells in a Wnt-signal-dependent manner via inhibiting the activation of glycogen synthase kinase-3β after phosphatidylinositol 3-kinase/protein kinase B signal activation, thereby activating Wnt1, β-catenin, and the expression of downstream neurogenic differentiation 1 and cyclin D1, which was comparable to Wnt/β-catenin signaling agonist 4,6-disubstituted pyrrolopyrimidine. We conclude that XQ-1H, after OGD/R damage to PC12 cells, may limit cell apoptosis in a Wnt/β-catenin signal-dependent manner, promoting cell proliferation and survival.

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A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1 mice

Cited by 34 publications

References 64 publications

Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

XQ‐1H attenuates ischemic injury in PC12 cells via Wnt/β‐catenin signaling though inhibition of apoptosis and promotion of proliferation

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