Vascular defects of<i>DYRK1A</i>knockouts are ameliorated by modulating calcium signaling in zebrafish

Lee, Jeong-Soo; Cho, Hyun-Ju; Lee, Jae-Geun; Kim, Jong-Hwan; Kim, Seon‐Young; Huh, Yang Hoon; Kim, Hyo-Jeong; Lee, Kyu-Sun; Yu, Kweon

doi:10.1101/349985

Cited by 4 publications

(4 citation statements)

References 87 publications

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“…across multiple or all backgrounds analyzed here, modulated the expression of genes implicated in organic acid metabolism and pathogen defense. Indeed, similar GO terms, such as "metabolic process" and "immune system process" were also detected in published gene expression studies on the mbk-1 ortholog in other systems, including zebrafish embryos [41], and HeLa cells [42]. Collectively, these data provide evidence for mbk-1/DYRK1A playing an evolutionarily conserved role in these processes.…”

Section: Genes and Pathways Deregulated Upon Loss Of Mbk-1supporting

confidence: 70%

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

et al. 2022

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Background In the nematode Caenorhabditis elegans, longevity in response to germline ablation, but not in response to reduced insulin/IGF1-like signaling, is strongly dependent on the conserved protein kinase minibrain-related kinase 1 (MBK-1). In humans, the MBK-1 ortholog DYRK1A is associated with a variety of disorders, most prominently with neurological defects observed in Down syndrome. To better understand mbk-1’s physiological roles and their dependence on genetic background, we analyzed the influence of mbk-1 loss on the transcriptomes of wildtype and long-lived, germline-deficient or insulin-receptor defective, C. elegans strains by RNA-sequencing. Results mbk-1 loss elicited global changes in transcription that were less pronounced in insulin-receptor mutant than in germline-deficient or wildtype C. elegans. Irrespective of genetic background, mbk-1 regulated genes were enriched for functions in biological processes related to organic acid metabolism and pathogen defense. qPCR-studies confirmed mbk-1 dependent induction of all three C. elegans Δ9-fatty acid desaturases, fat-5, fat-6 and fat-7, in wildtype, germline-deficient and insulin-receptor mutant strains. Conversely, mbk-1 dependent expression patterns of selected pathogen resistance genes, including asp-12, dod-24 and drd-50, differed across the genetic backgrounds examined. Finally, cth-1 and cysl-2, two genes which connect pathogen resistance to the metabolism of the gaseous messenger and lifespan regulator hydrogen sulfide (H2S), were commonly suppressed by mbk-1 loss only in wildtype and germline-deficient, but not in insulin-receptor mutant C. elegans. Conclusion Our work reveals previously unknown roles of C. elegans mbk-1 in the regulation of fatty acid desaturase- and H2S metabolic-genes. These roles are only partially dependent on genetic background. Considering the particular importance of fatty acid desaturation and H2S for longevity of germline-deficient C. elegans, we propose that these processes at least in part account for the previous observation that mbk-1 preferentially regulates lifespan in these worms.

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Section: Genes and Pathways Deregulated Upon Loss Of Mbk-1supporting

confidence: 70%

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

et al. 2022

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“…Interestingly, we found significantly decreased DYRK1A transcripts in calcium treated Tregs. A previous study also reported that vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signalling in zebrafish [24], suggesting that DYRK1A can also serve as potential target for developing Treg based therapeutics of GV. To the best of our knowledge, we could not find any reports which suggests that calcium treatment can modulate GSK3B levels and activity and hence we assessed the effect of calcium treatment on GSK3B levels and activity.…”

Section: Discussionmentioning

confidence: 95%

Calcium controlled NFATc1 activation enhances suppressive capacity of regulatory T cells isolated from generalized vitiligo patients

Giri

Bharti²,

Begum

et al. 2022

Immunology

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NFATs and FOXP3 are linked with impaired regulatory T-cells (Tregs) in generalized vitiligo (GV). To elucidate calcium mediated NFATc1 signalling pathway and its effect on Treg suppressive capacity in GV. Calcium levels, calcineurin, NFATc1 and GSK-3β activity and cell proliferation were assessed in 52 GV patients and 50 controls by calcium assay kit, calcineurin phosphatase assay kit, TransAM NFATc1 kit, GSK-3β ELISA and BrdU cell proliferation assay. Transcripts (CNB, CAM, GSK3B, DYRK1A and calcium channel genes) and protein (IFN-γ, IL-10 and TGF-β) expressions were assessed by qPCR and ELISA, respectively. Reduced plasma and intracellular Tregs calcium levels and ORAI1 transcripts suggested altered calcium homeostasis in GV Tregs (p = 0.00387, p = 0.0048, p < 0.0001), which led to decreased calcineurin and NFATc1 activity in GV Tregs (p = 0.0299, p < 0.0001). CNB and CAM transcripts were reduced in GV Tregs (p < 0.0001, p = 0.0004). GSK-3β activity, GSK3B and DYRK1A transcripts significantly

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“…Novel inhibitors presumably with higher specificity still needs particular careful investigation regarding both efficiency and toxicity. A recent report has shown the influence of DRK1A inhibition on vascular dysfunction in the context of developing cerebral vasculature via regulation of calcium signalling, using a zebrafish model [31]. In our previous report, a similar 3D sandwich model demonstrated its potential application in angiogenesis study [16].…”

Section: Discussionmentioning

confidence: 89%

Minimalised Three-Dimensional Human Midbrain In Vitro Model for Neurotoxicity Evaluation of DYRK1 Inhibitors

Xiao¹,

Fagan²,

Brennan³

et al. 2022

Preprint

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The poor success rate of preclinical drugs which target the nervous system is related to the highly complex nature of brain physiology and pathophysiology. For in vitro drug screening in this field, the two-dimensional (2D) approach - where cells are incubated in a monolayer - is not physiologically relevant. In contrast, in vivo rodent models are very low throughput and expensive. As such, improved, well-characterised three dimensional (3D) in vitro models should be employed to bridge the gap between 2D in vitro primary screening and rodent models by incorporating aspects of the in vivo brain environment. These key features include the extracellular matrix (ECM) and a multidimensional relationship of supporting cells. In this study, a neural progenitor cell line was differentiated into the main types of cells found in brain, including neurons and astrocytes. This model was designed in a 3D extracellular matrix replacement in a minimalised manner. Different culture formats using multi-well plates were explored and a high-throughput cellular imaging platform was applied. Next, we applied this model to assess neural toxicity of a newly synthesised dual-specificity tyrosine-regulated kinase 1 (DYRK1) inhibitor derived from natural compounds, which is structurally related to a natural DYRK1A inhibitor harmine, K04179. Chemical studies have already shown that K04179 has higher specificity to DYRK1A compared with previously reported DYRK1 inhibitors, such as INDY. We have produced the first report of the biological effects of this new compound on the new 3D minimalised mid-brain model with quantification of both neuronal and astrocyte populations in tandem, revealing differential toxic effects of DYRK1 inhibitor compounds K04179 and INDY on neurons and glia.

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Vascular defects ofDYRK1Aknockouts are ameliorated by modulating calcium signaling in zebrafish

Cited by 4 publications

References 87 publications

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

Calcium controlled NFATc1 activation enhances suppressive capacity of regulatory T cells isolated from generalized vitiligo patients

Minimalised Three-Dimensional Human Midbrain In Vitro Model for Neurotoxicity Evaluation of DYRK1 Inhibitors

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