Compensatory Regulation of Dopamine after Ablation of the Tyrosine Hydroxylase Gene in the Nigrostriatal Projection

Tokuoka, Hirofumi; Muramatsu, Shin‐ichi; Sumi‐Ichinose, Chiho; Sakane, Hiroaki; Kojima, Masayo; Aso, Yoshinori; Nomura, T.; Metzger, Daniel; Ichinose, Hiroshi

doi:10.1074/jbc.m111.284729

Cited by 23 publications

(21 citation statements)

References 42 publications

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“…Our results along with reports of Cre toxicity in transgenic mice emphasize the importance of appropriate controls for Cre effects, seldom included in studies implicating Cremediated recombination. AAV-mediated Cre recombination is a common method to study gene function in the brain, including in the SN (Tokuoka et al 2011;Yu et al 2012), with viral titers often comparable to those used in our study (Yu et al 2012;Yeo and Herbison 2014;Shen et al 2016;Kopra et al 2017), but the local effects of Cre expression have been poorly investigated. Maintaining an appropriate balance between recombination of the target gene and toxicity is an important pitfall in studies using Cre recombinase.…”

Section: Discussionmentioning

confidence: 65%

“…AAV‐mediated Cre recombination is a common method to study gene function in the brain, including in the SN (Tokuoka et al . ; Yu et al . ), with viral titers often comparable to those used in our study (Yu et al .…”

Section: Discussionmentioning

confidence: 99%

“…A versatile method often used to study the function of genes in the adult brain is the injection of viral vectors mediating Cre expression (Kaspar et al 2002;Scammell et al 2003;Ahmed et al 2004;Lazarus et al 2011;Tokuoka et al 2011;Krenzer et al 2011;Kopra et al 2017;Bruchas et al 2011;Thanos et al 2012;Lee et al 2013;Yeo and Herbison 2014;Xia et al 2015;Mesic et al 2015;Whitney et al 2016;Foglesong et al 2016;Shen et al 2016). However, the possible noxious effects of Cre per se in this experimental setup have seldom been considered.…”

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confidence: 99%

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Viral vector‐mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine‐related behaviors and hallmarks of programmed cell death

Amin

Gruszczynski

Guiard

et al. 2019

Journal of Neurochemistry

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Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre‐expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP‐like sites present in the genome. However, most studies reporting the consequences of Cre‐lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data. In this study, we report the anatomical, neurochemical, and behavioral consequences in mice of adeno‐associated virus (AAV)‐mediated Cre expression in the dopaminergic nuclei substantia nigra, at commonly used viral titers (3 × 109 genome copies/0.3 μL or 2 × 109 genome copies/0.6 μL). We found that injecting AAV‐eGFP‐Cre into the SN engendered drastic and reproducible modifications of behavior, with increased basal locomotor activity as well as impaired locomotor response to cocaine compared to AAV‐eGFP‐injected controls. Cre expression in the SN induced a massive decrease in neuronal populations of both pars compacta and pars reticulata and dopamine depletion in the nigrostriatal pathway. This anatomical injury was associated with typical features of programmed cell death, including an increase in DNA break markers, evidence of apoptosis, and disrupted macroautophagy. These observations underscore the need for careful control of Cre toxicity in the brain and the reassessment of previous studies. In addition, our findings suggest that Cre‐mediated ablation may constitute an efficient tool to explore the function of specific cell populations and areas in the brain, and the impact of neurodegeneration in these populations.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Viral vector‐mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine‐related behaviors and hallmarks of programmed cell death

Amin

Gruszczynski

Guiard

et al. 2019

Journal of Neurochemistry

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“…It is possible that there are compensatory mechanisms that have yet to be explained in Jam-b-deficient animals; however, these were not evident in our aortic explant studies where an effect was observed. Such compensatory mechanisms have been showninotherdiseasemodels-for example, in the mouse brain when tyrosine hydrolase is inactivated (61) or in prostate cancer cell lines when Bcl-2 is down-regulated (62). Another hypothesis is that JAM-B could be necessary for inflammatory angiogenesis (63) (64) rather that tumor angiogenesis.…”

Section: In Vivo Jam-b Targeting Does Not Impact On Tumor Developmentmentioning

confidence: 98%

Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling

Meguenani¹,

Miljkovic‐Licina²,

Fagiani³

et al. 2015

The FASEB Journal

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De novo formation of blood vessels is a pivotal mechanism during cancer development. During the past few years, antiangiogenic drugs have been developed to target tumor vasculature. However, because of limitations and adverse effects observed with current therapies, there is a strong need for alternative antiangiogenic strategies. Using specific anti-junctional adhesion molecule (JAM)-B antibodies and Jam-b-deficient mice, we studied the role in antiangiogenesis of JAM-B. We found that antibodies against murine JAM-B, an endothelium-specific adhesion molecule, inhibited microvessel outgrowth from ex vivo aortic rings and in vitro endothelial network formation. In addition, anti-JAM-B antibodies blocked VEGF signaling, an essential pathway for angiogenesis. Moreover, increased aortic ring branching was observed in aortas isolated from Jam-b-deficient animals, suggesting that JAM-B negatively regulates proangiogenic pathways. In mice, JAM-B expression was detected in de novo-formed blood vessels of tumors, but anti-JAM-B antibodies unexpectedly did not reduce tumor growth. Accordingly, JAM-B deficiency in vivo had no impact on blood vessel formation, suggesting that targeting JAM-B in vivo may be offset by other proangiogenic mechanisms. In conclusion, despite the promising effects observed in vitro, targeting JAM-B during tumor progression seems to be inefficient as a stand-alone antiangiogenesis therapy.

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“…In a recent study, ablation of the TH gene in mice revealed that TH protein levels in the axon terminals are regulated differently from that in the soma, and that tissue dopamine levels are under trans-axonal compensatory regulation: The reduction of dopamine in some axons induces enhanced dopamine synthesis in others (Tokuoka et al, 2011). Trans-axonal compensation may be mediated by phsophorylation of TH, decreased dopamine reuptake or by neurotrophic factors.…”

Section: Compensatory Mechanisms In Presymptomatic and Early Pd Diseasementioning

confidence: 99%

Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease

Greenbaum¹,

Lorberboym²,

Melamed³

et al. 2013

Front. Neurosci.

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Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS), and extensive Nigro-Striatal (NS) degeneration, manifested by reduced uptake of [123I]FP-CIT, is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small “proof of concept” study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

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Compensatory Regulation of Dopamine after Ablation of the Tyrosine Hydroxylase Gene in the Nigrostriatal Projection

Cited by 23 publications

References 42 publications

Viral vector‐mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine‐related behaviors and hallmarks of programmed cell death

Viral vector‐mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine‐related behaviors and hallmarks of programmed cell death

Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling

Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease

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