References of "Peers, Bernard"
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See detailCodon-specific translation reprogramming promotes resistance to targeted therapy
Rapino, Francesca ULiege; Delaunay, Sylvain ULiege; Rambow, Florian et al

in Nature (2018), 558

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ... [more ▼]

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. [less ▲]

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See detailPancreatic delta cells could be a new source of beta cells in adult zebrafish
Carril Pardo, Claudio Andrès ULiege; Bergemann, David ULiege; Massoz, Laura ULiege et al

Poster (2018, June 04)

Diabetes occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and ... [more ▼]

Diabetes occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Several observations of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the pancreas could be harnessed in future therapies. Notably, endocrine alpha- and delta-cells have been shown in mouse to convert or transdifferentiate into beta-cell after massive destruction in adult and juvenile, respectively [1] [2]. Due to its potent regenerative capabilities, zebrafish, unlike mammals, is a model of choice to dissect the cellular and molecular mechanisms underlying beta-cell regeneration. Using a chemogenetic model to induce selective destruction of beta-cells, we recently showed that adult zebrafish duct cells display characteristics of embryonic pancreatic progenitors and that they can give rise to beta-cells in physiological and induced diabetic condition [3]. In this study we pretend to search new sources of beta cell regeneration and understand the underlying molecular and cellular basis in zebrafish. Indeed, recent observations in our laboratory reveal the appearance of bi-hormonal Somatostatin/Insulin (Sst/ Ins) cells during beta-cell regeneration in adult zebrafish. This suggests 1) other cellular origins of the regenerated beta-cells, ie the endocrine delta-cells that express somatostatin (Sst) or 2) that regenerated beta-cells display different features as compared to the original ones. To assess both possibilities, we analyzed these bi-hormonal cells at different time points during regeneration and at different ages. Here, we show the appearance of bi-hormonal cells (Sst/ Ins) after beta-cell ablation in embryos and larvae in the regeneration stage, similar to those observed in adult fish. Transcriptomic analyses from adult zebrafish further show that at least some regenerated beta cells have poly-hormonal characteristics corresponding to other pancreatic and non-pancreatic endocrine cells. We are currently investigating whether these features affect the function of the regenerated beta-cells and if delta-cells give rise to new betacells in zebrafish by lineage tracing studies. [less ▲]

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See detailIdentification of Pax6-dependent regulatory networks during endocrine pancreatic cells and enteroendocrine cells differentiation in zebrafish
Lavergne, Arnaud ULiege; Tarifeno, Estefania; Pirson, Justine et al

Poster (2018, April 09)

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See detailNifurpirinol : a more potent and reliable substrate compared to metronidazole for nitroreductase-mediated cell ablations.
Bergemann, David ULiege; Massoz, Laura ULiege; Bourdouxhe, Jordane ULiege et al

in Wound Repair and Regeneration (2018)

The zebrafish is a popular animal model with well-known regenerative capabilities. To study regeneration in this fish, the nitroreductase/metronidazole-mediated system is widely used for targeted ablation ... [more ▼]

The zebrafish is a popular animal model with well-known regenerative capabilities. To study regeneration in this fish, the nitroreductase/metronidazole-mediated system is widely used for targeted ablation of various cell types. Nevertheless, we highlight here some variability in ablation efficiencies with the metronidazole prodrug that led us to search for a more efficient and reliable compound. Herein, we present nifurpirinol, another nitroaromatic antibiotic, as a more potent prodrug compared to metronidazole to trigger cell-ablation in nitroreductase expressing transgenic models. We show that nifurpirinol induces robust and reliable ablations at concentrations 2000 fold lower than metronidazole and three times below its own toxic concentration. We confirmed the efficiency of nifurpirinol in triggering massive ablation of three different cell types: the pancreatic beta cells, osteoblasts and dopaminergic neurons. Our results identify nifurpirinol as a very potent prodrug for the nitroreductase-mediated ablation system and suggest that its use could be extended to many other cell types, especially if difficult to ablate, or when combined pharmacological treatments are desired. This article is protected by copyright. All rights reserved. [less ▲]

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See detailIdentification of Signaling Pathways Regulating Beta Cell Regeneration in Zebrafish
Massoz, Laura; Bergemann, David ULiege; Lavergne, Arnaud ULiege et al

Poster (2017, September 15)

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic ... [more ▼]

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Beta-cell neogenesis can be achieved from different pancreatic cell types leading to the hope that triggering regeneration could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells. We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that give rise to beta-cells in physiological and induced diabetic condition*. To better understand the molecular mechanisms underlying this potential, genes and signaling pathways regulated in the zebrafish pancreatic ducts after beta-cell ablation have been identified by transcriptomic profiling. For functional studies, we have developed an assay using 7-20 days old larvae to investigate the role of selected candidate pathways in beta-cell regeneration with pharmacological inhibitors/activators and by transgenic overexpression of candidate signaling factors. These results should provide new hints to help improve regenerative competences in mammals. [less ▲]

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See detailToward discovery of novel key genes for pancreatic beta cell regeneration in zebrafish
Carril Pardo, Claudio Andrès ULiege; Bergemann, David ULiege; Massoz, Laura ULiege et al

Poster (2017, September 14)

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic ... [more ▼]

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Several observations of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the pancreas could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells. We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that can give rise to beta-cells in physiological and induced diabetic condition*, and we determined the transcriptomic profile of zebrafish pancreatic ducts during beta-cell regeneration. To identify new genes crucial for beta-cell regeneration we plan to investigate the role of about 10 selected candidate genes by analyzing invalidating mutations created by CRISPR/Cas9. Their effect on beta-cell regeneration will be studied in 7-20 old larvae which we have established as experimental platform for functional studies. This project should help decipher the molecular mechanism of beta-cell regeneration. [less ▲]

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See detailIdentification of Pax6-dependent regulatory networks during endocrine pancreatic cells and enteroendocrine cells differentiation in zebrafish
Lavergne, Arnaud ULiege; Tarifeno, Estefania; Pirson, Justine et al

Poster (2017, September 14)

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See detailTcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration.
Facchinello, Nicola; Tarifeño-Saldivia, Estefania; Grisan, Enrico et al

in Scientific Reports (2017), 7(1), 9605

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See detailBeta Cell Regeneration in Zebrafish : Investigating the Ductal Contribution
Bergemann, David ULiege; Massoz, Laura; Bourdouxhe, Jordane ULiege et al

Poster (2017, July)

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous ... [more ▼]

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous beta cells. One promising alternative is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have shown beta cell neogenesis originating from different pancreatic cell types (alpha, delta, acinar and ductal cells), depending on the used model. The ductal origin is supported by the fact that the embryonic duct epithelium gives rise to the endocrine lineage, and that in healthy and diabetic human adults, insulin positive cells could be found next to or in pancreatic ducts. Despite these observations, mammals show very limited regenerative capabilities, making it difficult to investigate those mechanisms. In contrast, zebrafish are extensively used for regeneration studies. The ability of adult zebrafish to regenerate its beta cells and restore normoglycemia after massive beta cell ablation has already been shown. We, and other groups, have previously shown that adult pancreatic duct cells act as progenitors, giving rise to beta cells in physiological and induced diabetic condition in vivo. To get insight into this process, we conducted comparative RNA-seq experiments on pancreatic duct cells from adult zebrafish. By this means, we identified regulated gene expression that can be linked to specific processes/pathways such as cell cycling and Notch. In order to confirm the involvement of identified candidate genes/pathways, we are setting up a screening method using chemical activators and inhibitors in old larvae, by looking at their ability to modify proliferation/differentiation of duct cells after beta cell ablation. In addition, we are also investigating the effect of mutations, generated by the CRISPR/Cas9 system within candidate genes, on the regeneration capabilities. Together, these strategies should provide new clues about regenerative processes triggered in duct cells that might be applied to overcome the poor regenerative capabilities of mammals. [less ▲]

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See detailComparison of pancreatic cell type transcriptomes across vertebrate species
Peers, Bernard ULiege

Conference (2017, May 08)

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See detailTranscriptome analysis of pancreatic cells across distant species highlights novel important regulator genes
Tarifeño-Saldivia, Estefania; Lavergne, Arnaud ULiege; Bernard, Alice ULiege et al

Conference (2017, March 21)

Detailed reference viewed: 22 (3 ULiège)
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See detailHabenular Neurogenesis in Zebrafish Is Regulated by a Hedgehog, Pax6 Proneural Gene Cascade
Halluin, Caroline; Madelaine, Romain; Naye, Francois et al

in PLoS ONE (2016), 11(7), 0158210

The habenulae are highly conserved nuclei in the dorsal diencephalon that connect the forebrain to the midbrain and hindbrain. These nuclei have been implicated in a broad variety of behaviours in humans ... [more ▼]

The habenulae are highly conserved nuclei in the dorsal diencephalon that connect the forebrain to the midbrain and hindbrain. These nuclei have been implicated in a broad variety of behaviours in humans, primates, rodents and zebrafish. Despite this, the molecular mechanisms that control the genesis and differentiation of neural progenitors in the habenulae remain relatively unknown. We have previously shown that, in zebrafish, the timing of habenular neurogenesis is left-right asymmetric and that in the absence of Nodal signalling this asymmetry is lost. Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4. We present evidence that Hedgehog signalling is required for the expression of pax6a, which is in turn necessary for the expression of neurog1 and neurod4. Finally, we demonstrate by pharmacological inhibition that Hedgehog signalling is required continuously during habenular neurogenesis and by cell transplantation experiments that pathway activation is required cell autonomously. Our data sheds light on the mechanism underlying habenular development that may provide insights into how Nodal signalling imposes asymmetry on the timing of habenular neurogenesis. [less ▲]

Detailed reference viewed: 60 (2 ULiège)
See detailADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
Dupont, Laura ULiege; Janssen, Lauriane; Bekhouche, Mourad et al

Conference (2016, June)

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See detailPancreatic Beta Cell Regeneration: Duct Cells Act as Progenitors in Adult Zebrafish
Bergemann, David ULiege; Ghaye, Aurélie; Tarifeño Saldivia, Estefania ULiege et al

Poster (2016, March 18)

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous ... [more ▼]

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous beta cells. One promising alternative is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have shown beta cell neogenesis but still remain controversial about their origin as they used different models. However, among the different hypotheses, it is tempting to assume that pancreatic ducts contain progenitor/precursor cells in adults. The latter is supported by the fact that the embryonic duct epithelium gives rise to the endocrine lineage, and that in healthy and diabetic human adults, insulin positive cells could be found next to or in pancreatic ducts. Despite these observations, mammals show very limited regenerative capabilities, making it difficult to investigate those mechanisms. In contrast, zebrafish are extensively used for regeneration studies. The ability of adult zebrafish to regenerate its beta cells and restore normoglycemia after massive beta cell ablation has already been shown. Our work focuses on the understanding of the underlying mechanisms leading to this retained potential. Here we show that adult pancreatic duct cells act as progenitors, giving rise to beta cells, in physiological and induced diabetic condition in vivo. To get insight into this process, we conducted RNA-seq experiments on zebrafish pancreatic duct cells. By this mean we could identify new ductal markers and noticed that adult duct cells also show strong expression of embryonic pancreatic progenitor markers. In our ongoing comparative analyses we are deciphering the key genes and pathways needed to set in motion the regenerative machinery. The differences between zebrafish and mammal duct cells that will thereby be underlined might then be transposed to mammalian model s to restore regenerative processes. [less ▲]

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See detailPhenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity
Verstraelen,, Sandra; Peers, Bernard ULiege; Maho, w et al

in Journal of Applied Toxicology (2016)

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See detailPancreatic Beta Cell Regeneration: Duct Cells act as Progenitors in Adult Zebrafish
Bergemann, David ULiege; Ghaye, Aurélie; Tarifeño, Estefania et al

Poster (2015, November)

Diabetes is characterized by the loss of insulin-producing beta cells. One promising therapeutic approach is to replenish the pancreas with bona fide functional beta cells by triggering regeneration ... [more ▼]

Diabetes is characterized by the loss of insulin-producing beta cells. One promising therapeutic approach is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have reported beta cell neogenesis but still remain controversial about their origin and are hampered by very limited regenerative capabilities of mammals. This is contrasting with the astonishing ability of zebrafish to spon-taneously regenerate its beta cells and restore normoglycemia after massive beta cell ablation1. Among the different pancreatic cell types, duct cells have been proposed as a promising source for beta cell replacement in regard to their progenitor capabilities during development. Our project focuses on the role of pancreatic duct cells and the molecular mechanisms involved during beta cell regeneration in adult Zebrafish. To that end we used and de-veloped tools to analyze pancreatic duct cells in normal and regenerating conditions and conducted RNA-sequencing experiments. [less ▲]

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