MFng Is Dispensable for Mouse Pancreas Development and Function

ABSTRACT Notch signaling regulates pancreatic cell differentiation, and mutations of various Notch signaling components result in perturbed pancreas development. Members of the Fringe family of β1,3-N-acetylglucosaminyltransferases, Manic Fringe (MFng), Lunatic Fringe (LFng), and Radical Fringe (RFng), modulate Notch signaling, and MFng has been suggested to regulate pancreatic endocrine cell differentiation. We have characterized the expression of the three mouse Fringe genes in the developing mouse pancreas between embryonic days 9 and 14 and show that the expression of MFng colocalized with the proendocrine transcription factor Ngn3. In contrast, the expression of LFng colocalized with the exocrine marker Ptf1a, whereas RFng was not expressed. Moreover, we show that expression of MFng is lost in Ngn3 mutant mice, providing evidence that MFng is genetically downstream of Ngn3. Gain- and loss-of-function analyses of MFng by the generation of mice that overexpress MFng in early pancreatic progenitor cells and mice with a targeted deletion of MFng provide, however, evidence that MFng is dispensable for pancreas development and function, since no pancreatic defects in these mice were observed.

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Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-mediated Repression

10.1101/336305 ◽

2018 ◽

Cited By ~ 5

Author(s):

Kristian H. de Lichtenberg ◽

Philip A. Seymour ◽

Mette C. Jørgensen ◽

Yung-Hae Kim ◽

Anne Grapin-Botton ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Target Genes ◽

Specific Gene ◽

Pancreatic Cell ◽

Pancreatic Progenitor ◽

Endocrine Differentiation ◽

Pancreatic Progenitor Cells ◽

Genes Encoding ◽

Direct Target

AbstractNotch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq analysis of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks associated with 354 genes. Among these were genes important for tip/trunk segregation such asPtf1aandNkx6-1, genes involved in endocrine differentiation such asInsm1andDll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such asNeurog2andAscl1. Surprisingly, we find that Hes1 binds a large number of loci previously reported to bind Ptf1a, including a site downstream of theNkx6-1gene. Notably, we find a number of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently ofNeurog3function, including the tip progenitor/acinar genes;Ptf1a, Gata4, Bhlha15, andGfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new molecular targets of Notch signaling that may be important for controlling cell fate choices in pancreas development.

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Regulation of Pancreatic Juxtaductal Endocrine Cell Formation by FoxO1

Molecular and Cellular Biology ◽

10.1128/mcb.01622-08 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4417-4430 ◽

Cited By ~ 42

Author(s):

Tadahiro Kitamura ◽

Yukari Ido Kitamura ◽

Masaki Kobayashi ◽

Osamu Kikuchi ◽

Tsutomu Sasaki ◽

...

Keyword(s):

Progenitor Cells ◽

Endocrine Cell ◽

Cell Formation ◽

Diabetic Patients ◽

Loss Of Function ◽

Β Cells ◽

Pancreatic Cell ◽

Pancreatic Progenitor ◽

Endocrine Differentiation ◽

Pancreatic Progenitor Cells

ABSTRACT An understanding of the mechanisms that govern pancreatic endocrine cell ontogeny may offer strategies for their somatic replacement in diabetic patients. During embryogenesis, transcription factor FoxO1 is expressed in pancreatic progenitor cells. Subsequently, it becomes restricted to β cells and to a rare population of insulin-negative juxtaductal cells (FoxO1+ Ins−). It is unclear whether FoxO1+ Ins− cells give rise to endocrine cells. To address this question, we first evaluated FoxO1's role in pancreas development using gain- and loss-of-function alleles in mice. Premature FoxO1 activation in pancreatic progenitors promoted α-cell formation but curtailed exocrine development. Conversely, FoxO1 ablation in pancreatic progenitor cells, but not in committed endocrine progenitors or terminally differentiated β cells, selectively increased juxtaductal β cells. As these data indicate an involvement of FoxO1 in pancreatic lineage determination, FoxO1+ Ins− cells were clonally isolated and assayed for their capacity to undergo endocrine differentiation. Upon FoxO1 activation, FoxO1+ Ins− cultures converted into glucagon-producing cells. We conclude that FoxO1+ Ins− juxtaductal cells represent a hitherto-unrecognized pancreatic cell population with in vitro capability of endocrine differentiation.

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Isolation of Pancreatic Progenitor Cells with the Surface Marker of Hematopoietic Stem Cells

International Journal of Endocrinology ◽

10.1155/2012/948683 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Fengxia Ma ◽

Fang Chen ◽

Ying Chi ◽

Shaoguang Yang ◽

Shihong Lu ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Culture System ◽

Isolated Cells ◽

Pancreatic Cell ◽

Hematopoietic Stem ◽

Pancreatic Progenitor ◽

Pancreatic Progenitor Cells ◽

Embryonic Pancreas

To isolate pancreatic progenitor cells with the surface markers of hematopoietic stem cells, the expression of stem cell antigen (Sca-1) and c-Kit and the coexpression of them with pancreatic duodenal homeobox-1 (PDX-1), neurogenin 3 (Ngn3), and insulin were examined in murine embryonic pancreas. Then different pancreatic cell subpopulations were isolated by magnet-activated cell sorting. Isolated cells were cultured overnight in hanging drops. When cells formed spheres, they were laid on floating filters at the air/medium interface. With this new culture system, pancreatic progenitor cells were induced to differentiate to endocrine and exocrine cells. It was shown that c-Kit and Sca-1 were expressed differently in embryonic pancreas at 12.5, 15.5, and 17.5 days of gestation. The expression of c-Kit and Sca-1 was the highest at 15.5 days of gestation. c-Kit rather than Sca-1 coexpressed with PDX-1, Ngn3, and insulin. Cells differentiated from c-Kit-positive cells contained more insulin-producing cells and secreted more insulin in response to glucose stimulation than that from c-Kit-negative cells. These results suggested that c-Kit could be used to isolate pancreatic progenitor cells and our new culture system permitted pancreatic progenitor cells to differentiate to mature endocrine cells.

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Factors controlling pancreatic cell differentiation and function

Diabetologia ◽

10.1007/s001250100623 ◽

2001 ◽

Vol 44 (9) ◽

pp. 1071-1079 ◽

Cited By ~ 51

Author(s):

H. Edlund

Keyword(s):

Cell Differentiation ◽

Pancreatic Cell ◽

And Function

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A functional screen of translated pancreatic lncRNAs identifies a microprotein-independent role for LINC00261 in endocrine cell differentiation

10.1101/2020.04.28.062679 ◽

2020 ◽

Author(s):

Bjoern Gaertner ◽

Sebastiaan van Heesch ◽

Valentin Schneider-Lunitz ◽

Jana Felicitas Schulz ◽

Franziska Witte ◽

...

Keyword(s):

Cell Differentiation ◽

Endocrine Cell ◽

Small Scale ◽

List Type ◽

Pancreas Development ◽

Human Pancreas ◽

Loss Of Function ◽

Developmentally Regulated ◽

Small Proteins ◽

Heterogenous Group

AbstractLong noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Here, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated during pancreas development. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for endocrine cell differentiation. However, deletion of LINC00261 diminishes generation of insulin+ endocrine cells, in a manner independent of the nearby TF FOXA2. Systematic deletion of each of LINC00261’s seven poorly conserved microproteins shows that the RNA, rather than the microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs into recently evolved microproteins during human pancreas development and provides a blueprint for dissection of their coding and noncoding roles.Graphical AbstractHighlightsExtensive lncRNA translation and microprotein production during human pancreas developmentA small-scale loss-of-function screen shows most translated lncRNAs are dispensableLINC00261 is highly translated and regulates endocrine cell differentiationDeleting LINC00261’s evolutionary young microproteins reveals no essential roles

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Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors

10.1101/336529 ◽

2018 ◽

Author(s):

Philip A. Seymour ◽

Caitlin A. Collin ◽

Anuska l. R. Egeskov-Madsen ◽

Mette C. Jørgensen ◽

Hiromi Shimojo ◽

...

Keyword(s):

Notch Signaling ◽

Progenitor Cells ◽

Ductal Morphogenesis ◽

Pancreatic Progenitor ◽

Notch Activity ◽

Pancreatic Progenitors ◽

Pancreatic Progenitor Cells ◽

Acinar To Ductal Metaplasia ◽

Induced Changes ◽

Experimentally Induced

SummaryNotch signaling controls proliferation of multipotent pancreatic progenitor cells (MPCs) and their segregation into bipotent progenitors (BPs) and unipotent pro-acinar cells (PACs). Here we uncover fast ultradian oscillations in the ligand Dll1, and the transcriptional effector Hes1, which proved crucial for MPC expansion. Conversely Jag1, a uniformly expressed ligand, curbed MPC growth, but as expression later segregated to PACs it proved critical for specifying all but the most proximal 5% of BPs, while BPs were entirely lost in Jag1, Dll1 double mutants. Moreover, experimentally induced changes in Hes1 oscillation parameters was associated with selective adoption of BP or PAC fates. Anatomically, ductal morphogenesis and organ architecture is minimally perturbed in Jag1 mutants until later stages, when ductal remodeling fails and signs of acinar-to-ductal metaplasia appear. Our study uncovers oscillating Notch activity in the developing pancreas, which along with modulation by Jag1 is required to coordinate MPC growth and fate.

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L-Leucine Alters Pancreatic -Cell Differentiation and Function via the mTor Signaling Pathway

Diabetes ◽

10.2337/db11-0765 ◽

2011 ◽

Vol 61 (2) ◽

pp. 409-417 ◽

Cited By ~ 40

Author(s):

L. Rachdi ◽

V. Aiello ◽

B. Duvillie ◽

R. Scharfmann

Keyword(s):

Cell Differentiation ◽

Signaling Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Pancreatic Cell ◽

And Function

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Forkhead Protein FoxO1 Acts as a Repressor to Inhibit Cell Differentiation in Human Fetal Pancreatic Progenitor Cells

Journal of Diabetes Research ◽

10.1155/2017/6726901 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Zongzhe Jiang ◽

Jingjing Tian ◽

Wenjian Zhang ◽

Hao Yan ◽

Liping Liu ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Progenitor Cells ◽

Nude Mice ◽

Stem Cell Markers ◽

Cell Markers ◽

Pancreatic Progenitor ◽

Pancreatic Progenitor Cells ◽

In Vitro Induction

Our colleagues have reported previously that human pancreatic progenitor cells can readily differentiate into insulin-containing cells. Particularly, transplantation of these cell clusters upon in vitro induction for 3-4 w partially restores hyperglycemia in diabetic nude mice. In this study, we used human fetal pancreatic progenitor cells to identify the forkhead protein FoxO1 as the key regulator for cell differentiation. Thus, induction of human fetal pancreatic progenitor cells for 1 week led to increase of the pancreatic β cell markers such as Ngn3, but decrease of stem cell markers including Oct4, Nanog, and CK19. Of note, FoxO1 knockdown or FoxO1 inhibitor significantly upregulated Ngn3 and insulin as well as the markers such as Glut2, Kir6.2, SUR1, and VDCC, which are designated for mature β cells. On the contrary, overexpression of FoxO1 suppressed the induction and reduced expression of these β cell markers. Taken together, these results suggest that FoxO1 may act as a repressor to inhibit cell differentiation in human fetal pancreatic progenitor cells.

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