Zebrafish as a Genetic Model in Biological and Behavioral Gerontology: Where Development Meets Aging in Vertebrates – A Mini-Review

Kishi, Shuji; Slack, Barbara E.; Uchiyama, Junzō; Zhdanova, Irina V.

doi:10.1159/000228892

Cited by 75 publications

(58 citation statements)

References 142 publications

(91 reference statements)

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“…Cnc and Skn-1 have been reported to play a critical role in the regulation of life span in flies and worms, respectively (2,43), but the roles of Nrf2 in vertebrate longevity have not been sufficiently investigated (36). Recent studies have shown that the zebrafish is a potentially valuable model for aging research (12,24). The relationship between longevity and Nrf2 functions can be analyzed using the nrf2 fh318 mutants examined in this study.…”

Section: Fig 2 Survival Rate Of Nrf2mentioning

confidence: 98%

Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress

Mukaigasa

Nguyen

et al. 2012

Molecular and Cellular Biology

100

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bTranscription factor Nrf2 is considered a master regulator of antioxidant defense in mammals. However, it is unclear whether this concept is applicable to nonmammalian vertebrates, because no animal model other than Nrf2 knockout mice has been generated to examine the effects of Nrf2 deficiency. Here, we characterized a recessive loss-of-function mutant of Nrf2 (nrf2 fh318 ) in a lower vertebrate, the zebrafish (Danio rerio). In keeping with the findings in the mouse model, nrf2 fh318 mutants exhibited reduced induction of the Nrf2 target genes in response to oxidative stress and electrophiles but were viable and fertile, and their embryos developed normally. The nrf2 fh318 larvae displayed enhanced sensitivity to oxidative stress and electrophiles, especially peroxides, and pretreatment with an Nrf2-activating compound, sulforaphane, decreased peroxide-induced lethality in the wild type but not nrf2 fh318 mutants, indicating that resistance to oxidative stress is highly dependent on Nrf2 functions. These results reveal an evolutionarily conserved role of vertebrate Nrf2 in protection against oxidative stress. Interestingly, there were no significant differences between wild-type and nrf2 fh318 larvae with regard to their sensitivity to superoxide and singlet oxygen generators, suggesting that the importance of Nrf2 in oxidative stress protection varies based on the type of reactive oxygen species (ROS). Oxidative stress causes damage to multiple cellular components, such as DNA, proteins, and lipids, and is implicated in various human pathological conditions, including cancer, neurodegeneration, and inflammatory diseases (37). Several proteins such as superoxide dismutase (SOD), catalase, glutathione peroxidase (Gpx), peroxiredoxin (Prdx), and the small thiol molecules glutathione (GSH) and thioredoxin (Txn), are directly involved in the removal of oxidative stress. Recent discoveries in the cellular antioxidant system gave rise to the novel concept of "indirect antioxidants," which act through the augmentation of cellular antioxidant capacity by enhancing the gene expression driven by the transcription factor Nrf2 (21, 22). Nrf2 is a basic-region leucine zipper (bZIP) transcription factor that heterodimerizes with small Maf proteins and binds to the antioxidant response element (ARE) within the regulatory region of its target genes (20,27). A variety of cytoprotective genes that encode phase 2 detoxifying enzymes and antioxidant proteins, such as glutathione S-transferases (GST), NAD(P)H:quinone oxidoreductase, and glutamate-cysteine ligase, are induced by Nrf2 via ARE sequences (14). Under basal conditions, Nrf2 is constantly degraded through the ubiquitin-proteasome pathway in a Keap1-dependent manner (28, 50). Upon exposure to electrophiles or oxidative stress, Nrf2 escapes from proteasomal degradation, accumulates in the nucleus, and transcriptionally activates its target genes.We previously isolated zebrafish homologs of Nrf2 and its regulator Keap1 genes (nrf2, keap1a, and keap1b) and demonstrated that ...

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Section: Fig 2 Survival Rate Of Nrf2mentioning

confidence: 98%

Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress

Mukaigasa

Nguyen

et al. 2012

Molecular and Cellular Biology

100

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“…The recent and remarkable discovery that birds and reptiles lack the DAT transporter (Lovell et al, 2015) reduces the choice of vertebrate models to mammals and fish. Among those, the diurnal vertebrate zebrafish model offers multiple advantages, including its well-developed DA system (Panula et al, 2010), gradual aging (Kishi et al, 2009) and sensitivity to multiple drugs of abuse and their withdrawal (Bencan et al, 2009; López Patiño et al, 2008a; Riley et al, 2015; Rinkwitz et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Dopaminergic control of anxiety in young and aged zebrafish

Kacprzak

Patel

Riley

et al. 2017

Pharmacology Biochemistry and Behavior

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Changes in the expression of the dopamine transporter (DAT), or the sensitivity of dopamine receptors, are associated with aging and substance abuse and may underlie some of the symptoms common to both conditions. In this study, we explored the role of the dopaminergic system in the anxiogenic effects of aging and acute cocaine exposure by comparing the behavioral phenotypes of wildtype (WT) and DAT knockout zebrafish (DAT-KO) of different ages. To determine the involvement of specific dopamine receptors in anxiety states, antagonists to D1 (SCH23390) and D2/D3 (sulpiride) were employed. We established that DAT-KO results in a chronic anxiety-like state, seen as an increase in bottom-dwelling and thigmotaxis. Similar effects were produced by aging and acute cocaine administration, both leading to reduction in DAT mRNA abundance (qPCR). Inhibition of D1 activity counteracted the anxiety-like effects associated with DAT deficit, independent of its origin. Inhibition of D2/D3 receptors reduced anxiety in young DAT-KO, enhanced the anxiogenic effects of cocaine in WT, but did not affect aged WT or DAT-KO fish. These findings provide new evidence that the dopaminergic system plays a critical role in anxiety-like states, and suggest that adult zebrafish provide a sensitive diurnal vertebrate model for elucidating the molecular mechanisms of anxiety and a platform for anxiolytic drug screens.

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“…Likewise, transgenic mouse studies show that neurodegeneration itself may contribute to obesity [253]. Given the utility of zebrafish models to study aging [254,255], obesity (Tables 2 and 3) and neurodegeneration [256,257], it is possible to expect that novel aquatic models can be useful to mimic pathogenetic interplay between metabolic and neurodegenerative disorders. With the growing population affected by obesity, AD and PD worldwide [258], this direction of zebrafish biomedical research becomes especially timely and clinically relevant.…”

Section: Future Direction Of Researchmentioning

confidence: 99%