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Ahmed Mansouri - One of the best experts on this subject based on the ideXlab platform.
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Neurog3 misexpression unravels mouse pancreatic ductal Cell plasticity.
PloS one, 2018Co-Authors: Andhira Vieira, Bastien Vergoni, Monica Courtney, Noémie Druelle, Elisabet Gjernes, Biljana Hadzic, Fabio Avolio, Tiziana Napolitano, Sergi Navarro Sanz, Ahmed MansouriAbstract:In the context of type 1 diabetes research and the development of insulin-producing β-Cell replacement strategies, whether pancreatic ductal Cells retain their developmental capability to adopt an Endocrine Cell identity remains debated, most likely due to the diversity of models employed to induce pancreatic regeneration. In this work, rather than injuring the pancreas, we developed a mouse model allowing the inducible misexpression of the proEndocrine gene Neurog3 in ductal Cells in vivo. These animals developed a progressive islet hypertrophy attributed to a proportional increase in all Endocrine Cell populations. Lineage tracing experiments indicated a continuous neo-generation of Endocrine Cells exhibiting a ductal ontogeny. Interestingly, the resulting supplementary β-like Cells were found to be functional. Based on these findings, we suggest that ductal Cells could represent a renewable source of new β-like Cells and that strategies aiming at controlling the expression of Neurog3, or of its molecular targets/co-factors, may pave new avenues for the improved treatments of diabetes.
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Pax6 Inactivation in the Adult Pancreas Reveals Ghrelin as Endocrine Cell Maturation Marker.
PLoS ONE, 2014Co-Authors: Zeeshan Ahmad, Patrick Collombat, Maria Rafeeq, Ahmed MansouriAbstract:The transcription factor Pax6 is an important regulator of development and Cell differentiation in various organs. Thus, Pax6 was shown to promote neural development in the cerebral cortex and spinal cord, and to control pancreatic Endocrine Cell genesis. However, the role of Pax6 in distinct Endocrine Cells of the adult pancreas has not been addressed. We report the conditional inactivation of Pax6 in insulin and glucagon producing Cells of the adult mouse pancreas. In the absence of Pax6, beta- and alpha-Cells lose their molecular maturation characteristics. Our findings provide strong evidence that Pax6 is responsible for the maturation of beta-, and alpha-Cells, but not of delta-, and PP-Cells. Moreover, lineage-tracing experiments demonstrate that Pax6-deficient beta- and alpha-Cells are shunted towards ghrelin marked Cells, sustaining the idea that ghrelin may represent a marker for Endocrine Cell maturation.
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The Ectopic Expression of Pax4 in the Mouse Pancreas Converts Progenitor Cells into α and Subsequently β Cells
Cell, 2009Co-Authors: Patrick Collombat, Philippe Ravassard, Beatriz Sosa-pineda, Sébastien Dussaud, Nils Billestrup, Ole D. Madsen, Palle Serup, Harry Heimberg, Ahmed MansouriAbstract:Summary We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different Endocrine Cell subtypes in the mouse pancreas, without affecting the total Endocrine Cell numbers. Here, we conditionally and ectopically express Pax4 using different Cell-specific promoters and demonstrate that Pax4 forces Endocrine precursor Cells, as well as mature α Cells, to adopt a β Cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon + Cell neogenesis requiring the re-expression of the proEndocrine gene Ngn3 . However, the newly formed α Cells fail to correct the hypoglucagonemia since they subsequently acquire a β Cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in α Cells is capable of restoring a functional β Cell mass and curing diabetes in animals that have been chemically depleted of β Cells.
Isabella Artner - One of the best experts on this subject based on the ideXlab platform.
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retinol dehydrogenase 10 regulates pancreas organogenesis and Endocrine Cell differentiation via paracrine retinoic acid signaling
Endocrinology, 2016Co-Authors: Igor Arregi, Maria Climent, Dobromir Iliev, Jurgen Strasser, Nadege Gouignard, Jenny Johansson, Tania Singh, Magdalena Mazur, Henrik Semb, Isabella ArtnerAbstract:Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and Cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and Endocrine Cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagon+ and insulin+ Cells. During the secondary transition, the reduction of Neurogenin3+ Endocrine progenitors in t...
Marianne Voz - One of the best experts on this subject based on the ideXlab platform.
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ascl1b and neurod1 instead of neurog3 control pancreatic Endocrine Cell fate in zebrafish
BMC Biology, 2013Co-Authors: Lydie Flasse, Justine Pirson, David Stern, Virginie Von Berg, Isabelle Manfroid, Bernard Peers, Marianne VozAbstract: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.
Gérard Gradwohl - One of the best experts on this subject based on the ideXlab platform.
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Neurogenin3 is differentially required for Endocrine Cell fate specification in the intestinal and gastric epithelium
The EMBO Journal, 2002Co-Authors: Marjorie Jenny, Isabelle Duluc, Colette Roche, Jan Jensen, François Guillemot, Céline Uhl, Valérie Guillermin, Michèle Kedinger, Gérard GradwohlAbstract:Endocrine Cells of the pancreas and the gastrointestinal tract derive from multipotent endodermal stem Cells. We have shown previously that the basic helix– loop–helix (bHLH) transcription factor neurogenin3 (ngn3) is required for the specification of the Endocrine lineage in uncommitted progenitors in the developing pancreas. We investigate herein the expression and the function of ngn3 in the control of Endocrine Cell development in the intestinal and gastric epithelium. Our results indicate that as in the pancreas, gastrointestinal Endocrine Cells derive from ngn3-expressing progenitors. Mice homozygous for a null mutation in ngn3 fail to generate any intestinal Endocrine Cells, and Endocrine progenitor Cells are lacking. The other main intestinal epithelial Cell types differentiate properly. In contrast, in the glandular stomach, the differentiation of the gastrin- (G Cells) and somatostatin (D Cells)-secreting Cells is impaired whereas serotonin- (enterochromaffin EC Cells), histamine- (enterochromaffin-like ECL Cells) and ghrelin (X/A Cells)-expressing Cells are still present. Thus, ngn3 is strictly required for Endocrine Cell fate specification in multipotent intestinal progenitor Cells, whereas gastric Endocrine development is both ngn3 dependent and independent.
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neurogenin3 is required for the development of the four Endocrine Cell lineages of the pancreas
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Gérard Gradwohl, Andree Dierich, Marianne Lemeur, François GuillemotAbstract:In the mammalian pancreas, the Endocrine Cell types of the islets of Langerhans, including the α-, β-, δ-, and pancreatic polypeptide Cells as well as the exocrine Cells, derive from foregut endodermal progenitors. Recent genetic studies have identified a network of transcription factors, including Pdx1, Isl1, Pax4, Pax6, NeuroD, Nkx2.2, and Hlxb9, regulating the development of islet Cells at different stages, but the molecular mechanisms controlling the specification of pancreatic Endocrine precursors remain unknown. neurogenin3 (ngn3) is a member of a family of basic helix–loop–helix transcription factors that is involved in the determination of neural precursor Cells in the neuroectoderm. ngn3 is expressed in discrete regions of the nervous system and in scattered Cells in the embryonic pancreas. We show herein that ngn3-positive Cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic Endocrine Cells. Mice lacking ngn3 function fail to generate any pancreatic Endocrine Cells and die postnatally from diabetes. Expression of Isl1, Pax4, Pax6, and NeuroD is lost, and Endocrine precursors are lacking in the mutant pancreatic epithelium. Thus, ngn3 is required for the specification of a common precursor for the four pancreatic Endocrine Cell types.
Catherine Lee May - One of the best experts on this subject based on the ideXlab platform.
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nkx2 2 and arx genetically interact to regulate pancreatic Endocrine Cell development and Endocrine hormone expression
Developmental Biology, 2011Co-Authors: Teresa L Mastracci, Crystal L Wilcox, Luis Arnes, Casandra Panea, Jeffrey A Golden, Catherine Lee MayAbstract:Nkx2.2 and Arx are essential pancreatic transcription factors. Nkx2.2 is necessary for the appropriate specification of the islet alpha, beta, PP and epsilon Cell lineages, whereas Arx is required to form the correct ratio of alpha, beta, delta and PP Cells. To begin to understand the cooperative functions of Nkx2.2 and Arx in the development of Endocrine Cell lineages, we generated progenitor Cell-specific deletions of Arx on the Nkx2.2 null background. The analysis of these mutants demonstrates that expansion of the ghrelin Cell population in the Nkx2.2 null pancreas is not dependent on Arx; however, Arx is necessary for the upregulation of ghrelin mRNA levels in Nkx2.2 mutant epsilon Cells. Alternatively, in the absence of Arx, delta Cell numbers are increased and Nkx2.2 becomes essential for the repression of somatostatin gene expression. Interestingly, the dysregulation of ghrelin and somatostatin expression in the Nkx2.2/Arx compound mutant (Nkx2.2null;ArxΔpanc) results in the appearance of ghrelin+/somatostatin+ co-expressing Cells. These compound mutants also revealed a genetic interaction between Nkx2.2 and Arx in the regulation of the PP Cell lineage; the PP Cell population is reduced when Nkx2.2 is deleted but is restored back to wildtype numbers in the Nkx2.2null;ArxΔpanc mutant. Moreover, conditional deletion of Arx in specific pancreatic Cell populations established that the functions of Arx are necessary in the Neurog3+ Endocrine progenitors. Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the Endocrine progenitor Cells that ensure the correct specification and regulation of Endocrine hormone-producing Cells.
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gut Endocrine Cell development
Molecular and Cellular Endocrinology, 2010Co-Authors: Catherine Lee May, Klaus H KaestnerAbstract:Endocrine Cells are scattered throughout the gastrointestinal mucosa from the stomach to the colon and constitute one of the largest Endocrine systems in the body. EnteroEndocrine Cells labeled by chromogranin A comprise about 1% of all epithelial Cells in the gastrointestinal tract and are surrounded by mucus, chief, and parietal Cells in the stomach, and enterocyte, goblet and Paneth Cells in the intestine (Figure 1). The enteroEndocrine system consists of at least 15 different Cell types that can be classified based on their main hormonal products and on the ultrastructure of their secretory granules [1]. A given enteroEndocrine Cell secretes one or more hormone or hormone-like substance, which is released directly into the lamina propria and diffuses into the capillaries. These hormones include gastrin, histamine, serotonin, cholecystokinin (CCK), somatostatin and glucagon-like peptides (GLP1 and 2) [1]. Although enteroEndocrine Cells are very scarce, they are essential regulators of digestion, gut motility, appetite, and metabolism. Figure 1 Illustration of the major Cell types found in the gastrointestinal epithelium. Gastric epithelium contains mucus, chief, Parietal, and Endocrine Cells, whereas enterocyte, goblet, Endocrine, and Paneth Cells are found in the intestinal epithelium. Intestinal ... The development of enteroEndocrine Cells is a fascinating biological problem: how is the relative proportion of the individual subtypes maintained? How are so many different Cell types specified from a common precursor? And how is the Endocrine compartment maintained in the gastrointestinal epithelium with its rapid and life-long turnover? However, the study of the mechanisms of enteroEndocrine Cell differentiation is not only an “academic exercise” but of relevance to human health and disease on multiple levels. First, deficiencies in enteroEndocrine Cell specification or survival contribute to human diseases, as exemplified by congenital malabsorptive diarrhea, discussed in detail below, which is due solely to deficient enteroEndocrine Cells. Second, several enteroEndocrine Cells play a role the control of glucose homeostasis and thus diabetes, and there relatedness to pancreatic beta-Cells makes transdifferentiation of enteroEndocrine Cells an interesting possibility. Therefore, lessons learned from the study of normal gut Endocrine Cell development promise to be instructive to
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jagged1 is a competitive inhibitor of notch signaling in the embryonic pancreas
Mechanisms of Development, 2009Co-Authors: Maria L Golson, Catherine Lee May, John Le Lay, Nan Gao, Nuria C Bramswig, Kathleen M Loomes, Rebecca J Oakey, Peter White, Klaus H KaestnerAbstract:Pancreatic Endocrine Cells originate from precursors that express the transcription factor Neurogenin3 (Ngn3). Ngn3 expression is repressed by active Notch signaling. Accordingly, mice with Notch signaling pathway mutations display increased Ngn3 expression and Endocrine Cell lineage allocation. To determine how the Notch ligand Jagged1 (Jag1) functions during pancreas development, we deleted Jag1 in foregut endoderm and examined postnatal and embryonic Endocrine Cells and precursors. Postnatal Jag1 mutants display increased Ngn3 expression, α-Cell mass, and Endocrine Cell percentage, similar to the early embryonic phenotype of Dll1 and Rbpj mutants. However, in sharp contrast to postnatal animals, Jag1-deficient embryos display increased expression of Notch transcriptional targets and decreased Ngn3 expression, resulting in reduced Endocrine lineage allocation. Jag1 acts as an inhibitor of Notch signaling during embryonic pancreas development but an activator of Notch signaling postnatally. Expression of the Notch modifier Manic Fringe (Mfng) is limited to Endocrine precursors, providing a possible explanation for the inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development.