References of "Voz, Marianne"
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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 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 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 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 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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See detailThe bHLH transcription factor Ascl1a is essential for the specification of the intestinal secretory cells and mediates Notch signaling in the zebrafish intestine.
Flasse, Lydie C.; Stern, David ULiege; Pirson, Justine ULiege et al

in Developmental Biology (2013), 376(2), 187-97

Notch signaling has a fundamental role in stem cell maintenance and in cell fate choice in the intestine of different species. Canonically, Notch signaling represses the expression of transcription ... [more ▼]

Notch signaling has a fundamental role in stem cell maintenance and in cell fate choice in the intestine of different species. Canonically, Notch signaling represses the expression of transcription factors of the achaete-scute like (ASCL) or atonal related protein (ARP) families. Identifying the ARP/ASCL genes expressed in the gastrointestinal tract is essential to build the regulatory cascade controlling the differentiation of gastrointestinal progenitors into the different intestinal cell types. The expression of the ARP/ASCL factors was analyzed in zebrafish to identify, among all the ARP/ASCL factors found in the zebrafish genome, those expressed in the gastrointestinal tract. ascl1a was found to be the earliest factor detected in the intestine. Loss-of-function analyses using the pia/ascl1a mutant, revealed that ascl1a is crucial for the differentiation of all secretory cells. Furthermore, we identify a battery of transcription factors expressed during secretory cell differentiation and downstream of ascl1a. Finally, we show that the repression of secretory cell fate by Notch signaling is mediated by the inhibition of ascl1a expression. In conclusion, this work identifies Ascl1a as a key regulator of the secretory cell lineage in the zebrafish intestine, playing the same role as Atoh1 in the mouse intestine. This highlights the diversity in the ARP/ASCL family members acting as cell fate determinants downstream from Notch signaling. [less ▲]

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See detailEnteroendocrine cells ontogenesis in zebrafish
Stern, David ULiege; Voz, Marianne ULiege

Poster (2012, July 04)

Endocrine cells of the digestive tract include pancreatic cells clustered in the islets of Langerhans and the enteroendocrine cells, scattered throughout the digestive epithelium. Notch pathway plays a ... [more ▼]

Endocrine cells of the digestive tract include pancreatic cells clustered in the islets of Langerhans and the enteroendocrine cells, scattered throughout the digestive epithelium. Notch pathway plays a crucial role in endocrine cell fate determination and mediates cell fate decisions. The goal of this project is to decipher the molecular cascade triggered by Notch signaling that controls the endocrine cell differentiation in the digestive system. The targets of Notch signaling are usually members of the bHLH family and more precisely of the Achaete scute-like (Ascl) family or of the atonal related proteins (ARP) family. In this study, we searched for all ARP and Ascl factors expressed in the endocrine lineage of the pancreas and in the gastrointestinal tract in zebrafish.   [less ▲]

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See detailEssential roles of zebrafish bmp2a, fgf10 and fgf24 in the specification of the ventral pancreas
Naye, François ULiege; Voz, Marianne ULiege; Detry, Nathalie ULiege et al

in Molecular Biology of the Cell (2012)

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See detailPax4 is not essential for beta-cell differentiation in zebrafish embryos but modulates alpha-cell generation by repressing arx gene expression.
Djiotsa, Joachim; Verbruggen, Vincianne; Giacomotto, Jean et al

in BMC Developmental Biology (2012), 12

BACKGROUND: Genetic studies in mouse have demonstrated the crucial function of PAX4 in pancreatic cell differentiation. This transcription factor specifies beta- and delta-cell fate at the expense of ... [more ▼]

BACKGROUND: Genetic studies in mouse have demonstrated the crucial function of PAX4 in pancreatic cell differentiation. This transcription factor specifies beta- and delta-cell fate at the expense of alpha-cell identity by repressing Arx gene expression and ectopic expression of PAX4 in alpha-cells is sufficient to convert them into beta-cells. Surprisingly, no Pax4 orthologous gene can be found in chicken and Xenopus tropicalis raising the question of the function of pax4 gene in lower vertebrates such as in fish. In the present study, we have analyzed the expression and the function of the orthologous pax4 gene in zebrafish. RESULTS: pax4 gene is transiently expressed in the pancreas of zebrafish embryos and is mostly restricted to endocrine precursors as well as to some differentiating delta- and epsilon-cells but was not detected in differentiating beta-cells. pax4 knock-down in zebrafish embryos caused a significant increase in alpha-cells number while having no apparent effect on beta- and delta-cell differentiation. This rise of alpha-cells is due to an up-regulation of the Arx transcription factor. Conversely, knock-down of arx caused to a complete loss of alpha-cells and a concomitant increase of pax4 expression but had no effect on the number of beta- and delta-cells. In addition to the mutual repression between Arx and Pax4, these two transcription factors negatively regulate the transcription of their own gene. Interestingly, disruption of pax4 RNA splicing or of arx RNA splicing by morpholinos targeting exon-intron junction sites caused a blockage of the altered transcripts in cell nuclei allowing an easy characterization of the arx- and pax4-deficient cells. Such analyses demonstrated that arx knock-down in zebrafish does not lead to a switch of cell fate, as reported in mouse, but rather blocks the cells in their differentiation process towards alpha-cells. CONCLUSIONS: In zebrafish, pax4 is not required for the generation of the first beta- and delta-cells deriving from the dorsal pancreatic bud, unlike its crucial role in the differentiation of these cell types in mouse. On the other hand, the mutual repression between Arx and Pax4 is observed in both mouse and zebrafish. These data suggests that the main original function of Pax4 during vertebrate evolution was to modulate the number of pancreatic alpha-cells and its role in beta-cells differentiation appeared later in vertebrate evolution. [less ▲]

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See detailFast Homozygosity Mapping and Identification of a Zebrafish ENU-Induced Mutation by Whole-Genome Sequencing.
Voz, Marianne ULiege; Coppieters, Wouter ULiege; Manfroid, Isabelle ULiege et al

in PLoS ONE (2012), 7(4), 34671

Forward genetics using zebrafish is a powerful tool for studying vertebrate development through large-scale mutagenesis. Nonetheless, the identification of the molecular lesion is still laborious and ... [more ▼]

Forward genetics using zebrafish is a powerful tool for studying vertebrate development through large-scale mutagenesis. Nonetheless, the identification of the molecular lesion is still laborious and involves time-consuming genetic mapping. Here, we show that high-throughput sequencing of the whole zebrafish genome can directly locate the interval carrying the causative mutation and at the same time pinpoint the molecular lesion. The feasibility of this approach was validated by sequencing the m1045 mutant line that displays a severe hypoplasia of the exocrine pancreas. We generated 13 Gb of sequence, equivalent to an eightfold genomic coverage, from a pool of 50 mutant embryos obtained from a map-cross between the AB mutant carrier and the WIK polymorphic strain. The chromosomal region carrying the causal mutation was localized based on its unique property to display high levels of homozygosity among sequence reads as it derives exclusively from the initial AB mutated allele. We developed an algorithm identifying such a region by calculating a homozygosity score along all chromosomes. This highlighted an 8-Mb window on chromosome 5 with a score close to 1 in the m1045 mutants. The sequence analysis of all genes within this interval revealed a nonsense mutation in the snapc4 gene. Knockdown experiments confirmed the assertion that snapc4 is the gene whose mutation leads to exocrine pancreas hypoplasia. In conclusion, this study constitutes a proof-of-concept that whole-genome sequencing is a fast and effective alternative to the classical positional cloning strategies in zebrafish. [less ▲]

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See detailZebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration
Manfroid, Isabelle ULiege; Ghaye, Aurélie ULiege; Naye, François et al

in Developmental Biology (2012)

Recent zebrafish studies have shown that the late appearing pancreatic endocrine cells derive from pancreatic ducts but the regulatory factors involved are still largely unknown. Here, we show that the ... [more ▼]

Recent zebrafish studies have shown that the late appearing pancreatic endocrine cells derive from pancreatic ducts but the regulatory factors involved are still largely unknown. Here, we show that the zebrafish sox9b gene is expressed in pancreatic ducts where it labels the pancreatic Notchresponsive cells previously shown to be progenitors. Inactivation of sox9b disturbs duct formation and impairs regeneration of beta cells from these ducts in larvae. sox9b expression in the midtrunk endoderm appears at the junction of the hepatic and ventral pancreatic buds and, by the end of embryogenesis, labels the hepatopancreatic ductal system as well as the intrapancreatic and intrahepatic ducts. Ductal morphogenesis and differentiation are specifically disrupted in sox9b mutants, with the dysmorphic hepatopancreatic ducts containing misdifferentiated hepatocyte-like and pancreatic-like cells. We also show that maintenance of sox9b expression in the extrapancreatic and intrapancreatic ducts requires FGF and Notch activity, respectively, both pathways known to prevent excessive endocrine differentiation in these ducts. Furthermore, beta cell recovery after specific ablation is severely compromised in sox9b mutant larvae. Our data position sox9b as a key player in the generation of secondary endocrine cells deriving from pancreatic ducts in zebrafish. [less ▲]

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