Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

Rong, Xiaozhi; Zhou, Yumei; Liu, Yunzhang; Zhao, Beibei; Wang, Bo; Wang, Caixia; Gong, Xiaoxia; Tang, Peipei; Lü, Ling; Li, Yun; Zhao, Chengtian; Zhou, Jianfeng

doi:10.1242/dev.144261

Cited by 11 publications

(11 citation statements)

References 52 publications

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“…S1A ), we co-injected human VBP1 or zebrafish vbp1 mRNA and mRNA for wnt3a , β -cat Δ N , or vp16-tcf7l1 Δ N into zebrafish embryos. Consistent with a previous report ( 30 ), injection of wnt3a , β -cat Δ N , or vp16-tcf7l1 Δ N mRNA into zebrafish embryos resulted in dorsalized phenotypes at 12.5 hpf, which were neutralized by co-injection with either human VBP1 or zebrafish vbp1 mRNA, suggesting that the Wnt inhibitory action of VBP1/Vbp1 is evolutionarily conserved and acts at the TCF/LEF level ( Fig. 1 , F – I ).…”

Section: Resultssupporting

confidence: 92%

VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

Zhang

Rong

Wang

et al. 2020

Journal of Biological Chemistry

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The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor/lymphoid enhancer factor (TCF/LEF), serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL, and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provided mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

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Section: Resultssupporting

confidence: 92%

VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

Zhang

Rong

Wang

et al. 2020

Journal of Biological Chemistry

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“…Interestingly, Niemann-Pick C Disease-1 depleted embryos have impaired VitE trafficking and also have normal gsc expression at the same early timepoint 64 . Although modulation of lipid metabolism did not affect embryonic gsc expression 65 ; a ventralizing effect at the shield stage was observed with gpx4b knockdown, which increases www.nature.com/scientificreports/ oxidative damage by impairing lipid hydroperoxide detoxification 66 . E− embryos undergo normal gastrulation, which suggests that the oxidative damage due to VitE deficiency is insufficient to cause very early stage abnormalities.…”

Section: Discussionmentioning

confidence: 93%

Vitamin E is necessary for zebrafish nervous system development

Head

Tanguay

et al. 2020

Sci Rep

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Vitamin E (VitE) deficiency results in embryonic lethality. Knockdown of the gene ttpa encoding for the VitE regulatory protein [α-tocopherol transfer protein (α-TTP)] in zebrafish embryos causes death within 24 h post-fertilization (hpf). To test the hypothesis that VitE, not just α-TTP, is necessary for nervous system development, adult 5D strain zebrafish, fed either VitE sufficient (E+) or deficient (E−) diets, were spawned to obtain E+ and E− embryos, which were subjected to RNA in situ hybridization and RT-qPCR. Ttpa was expressed ubiquitously in embryos up to 12 hpf. Early gastrulation (6 hpf) assessed by goosecoid expression was unaffected by VitE status. By 24 hpf, embryos expressed ttpa in brain ventricle borders, which showed abnormal closure in E− embryos. They also displayed disrupted patterns of paired box 2a (pax2a) and SRY-box transcription factor 10 (sox10) expression in the midbrain-hindbrain boundary, spinal cord and dorsal root ganglia. In E− embryos, the collagen sheath notochord markers (col2a1a and col9a2) appeared bent. Severe developmental errors in E− embryos were characterized by improper nervous system patterning of the usually carefully programmed transcriptional signals. Histological analysis also showed developmental defects in the formation of the fore-, mid- and hindbrain and somites of E− embryos at 24 hpf. Ttpa expression profile was not altered by the VitE status demonstrating that VitE itself, and not ttpa, is required for development of the brain and peripheral nervous system in this vertebrate embryo model.

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“…In another recent report, the selenoenzyme Glutathione peroxidase 4 (GPX4) was shown to bind to TCFs and prevent their association with chromatin. The Wnt antagonistic functions of GPX4 were independent of its catalytic activity . Whether these factors are tissue/cell specific regulators or more broadly required for Wnt transcriptional regulation requires further study.…”

Section: Other Potential Factors Acting In the Switchmentioning

confidence: 98%

The Wnt Transcriptional Switch: TLE Removal or Inactivation?

et al. 2017

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Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a "transcriptional switch," repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway.

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Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

Cited by 11 publications

References 52 publications

VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

Vitamin E is necessary for zebrafish nervous system development

The Wnt Transcriptional Switch: TLE Removal or Inactivation?

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