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See detailMechanisms of cell fate specification by the ARP/ASCL factors in the zebrafish digestive system
Stern, David ULiege

Poster (2015, July 01)

Recently, we discovered that pancreatic endocrine cell fate in zebrafish is not controlled by Neurog3 like in mouse but by a couple of ARP/Ascl factors, Ascl1b and Neurod1. Furthermore, we identified ... [more ▼]

Recently, we discovered that pancreatic endocrine cell fate in zebrafish is not controlled by Neurog3 like in mouse but by a couple of ARP/Ascl factors, Ascl1b and Neurod1. Furthermore, we identified Ascl1a as the cell fate determinant of the secretory lineage in the zebrafish intestine while this function is fulfilled by Atoh1 in the murine intestine. These data highlighted a striking diversity in the ARP/Ascl factors involved in the determination and differentiation of the endocrine cells and showed that the choice of these factors depends not only on the organ considered but also on the species. The next question was to understand this diversity and determine whether these ARP/Ascl factors are interchangeable. We first test whether expression of Atoh1 could rescue the loss of secretory cells in the gut of the pia/ascl1a mutant by using the inducible transgenic lines Tg(hsp70:atoh1a) or Tg(Hsp70:atoh1b-Myc). We found that both lines can rescue efficiently the loss of secretory cells in the gut of the pia/ascl1a mutant. Furthermore, this rescue can be also obtained using two others ARP/ASCL factors, namely neurod1 or Ascl1b, suggesting that all these ARP/Ascl factors are interchangeable. However, the phenotype of the rescued embryos is slightly different from wild type embryos as they display an excess of goblet cells and a reduced number of enteroendocrine cells and we are currently investigating the reasons of such difference. Interestingly, we also found that the overexpression of Atho1 factors leads to ectopic endocrine cells in the liver and the anterior endoderm and the characterization of these ectopic cells will give insights about the mechanism of cell specification by the ARP/ASCL factors. [less ▲]

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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 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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