References of "Peers, Bernard"
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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

Conference (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 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 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 ▲]

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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 detailCopy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene
ishibashi, Minaka; Manning, Elisabeth; Shoubridge, Cheryl et al

in Human Genetics (2015), 134

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See detailProgenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration.
Ghaye, Aurelie P.; Bergemann, David ULiege; Tarifeño Saldivia, Estefania ULiege et al

in BMC biology (2015), 13

BACKGROUND: In contrast to mammals, the zebrafish has the remarkable capacity to regenerate its pancreatic beta cells very efficiently. Understanding the mechanisms of regeneration in the zebrafish and ... [more ▼]

BACKGROUND: In contrast to mammals, the zebrafish has the remarkable capacity to regenerate its pancreatic beta cells very efficiently. Understanding the mechanisms of regeneration in the zebrafish and the differences with mammals will be fundamental to discovering molecules able to stimulate the regeneration process in mammals. To identify the pancreatic cells able to give rise to new beta cells in the zebrafish, we generated new transgenic lines allowing the tracing of multipotent pancreatic progenitors and endocrine precursors. RESULTS: Using novel bacterial artificial chromosome transgenic nkx6.1 and ascl1b reporter lines, we established that nkx6.1-positive cells give rise to all the pancreatic cell types and ascl1b-positive cells give rise to all the endocrine cell types in the zebrafish embryo. These two genes are initially co-expressed in the pancreatic primordium and their domains segregate, not as a result of mutual repression, but through the opposite effects of Notch signaling, maintaining nkx6.1 expression while repressing ascl1b in progenitors. In the adult zebrafish, nkx6.1 expression persists exclusively in the ductal tree at the tip of which its expression coincides with Notch active signaling in centroacinar/terminal end duct cells. Tracing these cells reveals that they are able to differentiate into other ductal cells and into insulin-expressing cells in normal (non-diabetic) animals. This capacity of ductal cells to generate endocrine cells is supported by the detection of ascl1b in the nkx6.1:GFP ductal cell transcriptome. This transcriptome also reveals, besides actors of the Notch and Wnt pathways, several novel markers such as id2a. Finally, we show that beta cell ablation in the adult zebrafish triggers proliferation of ductal cells and their differentiation into insulin-expressing cells. CONCLUSIONS: We have shown that, in the zebrafish embryo, nkx6.1+ cells are bona fide multipotent pancreatic progenitors, while ascl1b+ cells represent committed endocrine precursors. In contrast to the mouse, pancreatic progenitor markers nkx6.1 and pdx1 continue to be expressed in adult ductal cells, a subset of which we show are still able to proliferate and undergo ductal and endocrine differentiation, providing robust evidence of the existence of pancreatic progenitor/stem cells in the adult zebrafish. Our findings support the hypothesis that nkx6.1+ pancreatic progenitors contribute to beta cell regeneration. Further characterization of these cells will open up new perspectives for anti-diabetic therapies. [less ▲]

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See detailComparative transcriptomic analysis of the distinct pancreatic cell types
Peers, Bernard ULiege

Conference (2015, June 28)

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See detailBiologie du développement (partim. animal)
Peers, Bernard ULiege

Learning material (2015)

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See detailADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
Janssen, Lauriane; Dupont, Laura; Bekhouche, Mourad ULiege et al

in Angiogenesis (2015)

The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens. A limited number of in vitro studies suggested ... [more ▼]

The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens. A limited number of in vitro studies suggested that ADAMTS3 is mainly responsible for procollagen II processing in cartilage. Here, we created an ADAMTS3 knockout mouse (Adamts3-/-) model to determine in vivo the actual functions of ADAMTS3. Heterozygous Adamts3+/- mice were viable and fertile, but their intercrosses demonstrated lethality of Adamts3-/- embryos after 15 days of gestation. Procollagens I, II and III processing was unaffected in these embryos. However, a massive lymphedema caused by the lack of lymphatics development, an abnormal blood vessel structure in the placenta and a progressive liver destruction were observed. These phenotypes are most probably linked to dysregulation of the VEGF-C pathways. This study is the first demonstration that an aminoprocollagen peptidase is crucial for developmental processes independently of its primary role in collagen biology and has physiological functions potentially involved in several human diseases related to angiogenesis and lymphangiogenesis. [less ▲]

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See detail“Transcriptome analysis by RNAseq of the distinct pancreatic cell types
Peers, Bernard ULiege

Conference (2014, March 30)

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See detailADAMTS-3 deficiency is embryonic lethal in mouse and zebrafish.
Janssen, Lauriane ULiege; Dubail, Johanne; Dupont, Laura ULiege et al

Conference (2013, November)

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See detailAscl1b and Neurod1, instead of Neurog3, control pancreatic endocrine cell fate in zebrafish
Flasse, Lydie; Pirson, Justine; Stern, David ULiege et al

in BMC Biology (2013), 11

Background NEUROG3 is a key regulator of pancreatic endocrine cell differentiation in mouse, essential for the generation of all mature hormone producing cells. It is repressed by Notch signaling that ... [more ▼]

Background NEUROG3 is a key regulator of pancreatic endocrine cell differentiation in mouse, essential for the generation of all mature hormone producing cells. It is repressed by Notch signaling that prevents pancreatic cell differentiation by maintaining precursors in an undifferentiated state. Results We show herein that, in zebrafish, neurog3 is not expressed in the pancreas and null neurog3 mutant embryos do not display any apparent endocrine defects. The control of endocrine cell fate is instead fulfilled by a couple of bHLH factors, Ascl1b and Neurod1, that are both repressed by Notch signaling. ascl1b is transiently expressed in the mid-trunk endoderm just after gastrulation and is required for the generation of the first pancreatic endocrine precursor cells. Neurod1 is expressed afterwards in the pancreatic anlagen and pursues the endocrine cell differentiation program initiated by Ascl1b. Their complementary role in endocrine differentiation of the dorsal bud is demonstrated by the loss of all hormone-secreting cells following their simultaneous inactivation. This defect is due to a blockage of the initiation of endocrine cell differentiation. Conclusions This study demonstrates that NEUROG3 is not the unique pancreatic endocrine cell fate determinant in vertebrates. A general survey of endocrine cell fate determinants in the whole digestive system among vertebrates indicates that they all belong to the ARP/ASCL family but not necessarily to the Neurog3 subfamily. The identity of the ARP/ASCL factor involved depends not only on the organ but also on the species. One could therefore consider differentiating stem cells into insulin-producing cells without the involvement of NEUROG3 but via another ARP/ASCL factor. [less ▲]

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See detailCharacterization of the zebrafish beta-cell transcriptome by RNA-seq
Manfroid, Isabelle ULiege; Tarifeño Saldivia, Estefania ULiege; Voz, Marianne ULiege et al

Poster (2013, May 27)

The loss of pancreatic insulin-producing cells (beta-cells) is a hallmark of diabetes and more knowledge is needed to find new treatments. Thus, it is crucial to identify novel regulatory genes ... [more ▼]

The loss of pancreatic insulin-producing cells (beta-cells) is a hallmark of diabetes and more knowledge is needed to find new treatments. Thus, it is crucial to identify novel regulatory genes specifically expressed in this pancreatic cell subtype. In the present study, the main pancreatic islet was dissected from transgenic Tg(insulin:GFP) adult zebrafish and beta-cells were selectively recovered by FACS with 98% of purity. Illumina RNA-seq was used to sequence the transcriptome. 20 millions of sequenced reads (paired-end) were obtained, aligned on the zebrafish genome and assembled into transcripts (Tophat/Cufflinks softwares). The zebrafish beta-cells transcriptome includes all known regulatory genes involved in beta-cell differentiation such as pdx1, mnx1, pax6b, neuroD, isl1, insm1, as well as Hopx and Hdac9 genes, both recently identified in human beta-cells. In contrast, the alpha-cell specific transcription factor arx and the acinar marker ptf1a were not detected, confirming the high purity of our beta-cell preparation. Interestingly, many miRNAs were detected, such as dre-mir-375 and dre-mir-7, as well as several lncRNA recently described at embryonic stages. We are currently applying the same approach to the Tg(somatostatin:GFP) and Tg(glucagon:GFP) transgenic lines in to characterize the transcriptome of delta- and alpha-cells. The comparison of these different data will allow us to identify coding and non-coding genes specifically expressed in the different endocrine subtype cells, paving the way for further functional studies. [less ▲]

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