scholarly journals A developmental lineage-based gene co-expression network for mouse pancreatic β-cells reveals a role for Zfp800 in pancreas development

Development ◽  
2021 ◽  
pp. dev.196964
Author(s):  
Anna B. Osipovich ◽  
Karrie D. Dudek ◽  
Emily Greenfest-Allen ◽  
Jean-Philippe Cartailler ◽  
Elisabetta Manduchi ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Zinc Finger Protein ◽  
Hormone Secretion ◽  
Protein Translation ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Expression Of Genes ◽  
Pancreatic Endocrine Cells ◽  
Exocrine Cell

To gain a deeper understanding of pancreatic β-cell development, we used iterativeWGCNA to calculate a gene co-expression network (GCN) from eleven temporally- and genetically-defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially-expressed during pancreas development. Pcdhγ is preferentially expressed in pancreatic endoderm, Pcdhβ in nascent islets, and Pcdhα in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. Zfp800 null mice exhibited early post-natal lethality, and at E18.5 their pancreata exhibited a reduced number of pancreatic endocrine cells, alterations in exocrine cell morphology, and marked changes in expression of genes involved in protein translation, hormone secretion, and developmental pathways in the pancreas. Together, our results suggest that developmentally-oriented GCNs have utility for gaining new insights into gene regulation during organogenesis.

scholarly journals Development and Characteristics of Pancreatic Epsilon Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1867 ◽  
Author(s):  
Naoaki Sakata ◽  
Gumpei Yoshimatsu ◽  
Shohta Kodama
Keyword(s):  
Transcription Factors ◽  
Blood Glucose ◽  
Endocrine Cells ◽  
Current Evidence ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Ghrelin Gene ◽  
Pancreatic Endocrine Cells

Pancreatic endocrine cells expressing the ghrelin gene and producing the ghrelin hormone were first identified in 2002. These cells, named ε cells, were recognized as the fifth type of endocrine cells. Differentiation of ε cells is induced by various transcription factors, including Nk2 homeobox 2, paired box proteins Pax-4 and Pax6, and the aristaless-related homeobox. Ghrelin is generally considered to be a “hunger hormone” that stimulates the appetite and is produced mainly by the stomach. Although the population of ε cells is small in adults, they play important roles in regulating other endocrine cells, especially β cells, by releasing ghrelin. However, the roles of ghrelin in β cells are complex. Ghrelin contributes to increased blood glucose levels by suppressing insulin release from β cells and is also involved in the growth and proliferation of β cells and the prevention of β cell apoptosis. Despite increasing evidence and clarification of the mechanisms of ε cells over the last 20 years, many questions remain to be answered. In this review, we present the current evidence for the participation of ε cells in differentiation and clarify their characteristics by focusing on the roles of ghrelin.

scholarly journals Tumour suppressor menin is essential for development of the pancreatic endocrine cells

2008 ◽  
Vol 199 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Sandra Fontanière ◽  
Bertrand Duvillié ◽  
Raphaël Scharfmann ◽  
Christine Carreira ◽  
Zhao-Qi Wang ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Endocrine Pancreas ◽  
Islet Cells ◽  
Specific Effect ◽  
Pancreas Development ◽  
Β Cells ◽  
Neurogenin 3 ◽  
Pancreatic Endocrine Cells ◽  
Endocrine Tissues

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene predispose patients to MEN1 that affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of Men1 in mice causes embryonic lethality, whereas the eventual involvement of the gene in embryonic development of the endocrine cells remains unknown. Here, we show that homozygous Men1 knockout mice demonstrate a reduced number of glucagon-positive cells in the E12.5 pancreatic bud associated with apoptosis, whereas the exocrine pancreas development in these mice is not affected. Our data suggest that menin is involved in the survival of the early pancreatic endocrine cells during the first developmental transition. Furthermore, chimerism assay revealed that menin has an autonomous and specific effect on the development of islet cells. In addition, using pancreatic bud culture mimicking the differentiation of α- and β-cells during the second transition, we show that loss of menin leads to the failure of endocrine cell development, altered pancreatic structure and a markedly decreased number of cells expressing neurogenin 3, indicating that menin is also required at this stage of the endocrine pancreas development. Taken together, our results suggest that menin plays an indispensable role in the development of the pancreatic endocrine cells.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

scholarly journals Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

2006 ◽  
Vol 26 (12) ◽  
pp. 4553-4563 ◽  
Author(s):  
Seon-Yong Yeom ◽  
Geun Hyang Kim ◽  
Chan Hee Kim ◽  
Heun Don Jung ◽  
So-Yeon Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Potential Role ◽  
Cell Mass ◽  
Dominant Negative ◽  
Transcriptional Coactivator ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

scholarly journals REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

2021 ◽  
Author(s):  
Meritxell Rovira ◽  
Goutham Atla ◽  
Miguel Angel Maestro ◽  
Vane Grau ◽  
Javier García-Hurtado ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Negative Regulator ◽  
Β Cell ◽  
Knock Out ◽  
Endocrine Differentiation ◽  
Conditional Allele ◽  
Embryonic Pancreas ◽  
Pancreatic Endocrine Cells ◽  
Knock Out Mice

SUMMARYUnderstanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreaticRestknock-out mice failed to show increased numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult duct-derived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation.

scholarly journals Human stem cell model of HNF1A deficiency shows uncoupled insulin to C-peptide secretion with accumulation of abnormal insulin granules

2021 ◽  
Author(s):  
Bryan J. González ◽  
Haoquan Zhao ◽  
Jacqueline Niu ◽  
Damian J. Williams ◽  
Jaeyop Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Insulin Secretion ◽  
Intracellular Calcium ◽  
Cell Fate ◽  
Endocrine Cells ◽  
Secretory Granules ◽  
Β Cells ◽  
C Peptide ◽  
Pancreatic Endocrine Cells

AbstractMutations in HNF1A cause Maturity Onset Diabetes of the Young type 3 (MODY3), the most prevalent form of monogenic diabetes. We generated stem cell-derived pancreatic endocrine cells from human embryonic stem cells (hESCs) with induced hypomorphic mutations in HNF1A. Using these cells, we show that HNF1A orchestrates a transcriptional program required for distinct aspects of β-cell fate and function. During islet cell differentiation, HNF1A deficiency biases islet endocrine cells towards an α-cell fate associated with PAX4 down-regulation. HNF1A- deficient β-cells display impaired basal and glucose stimulated-insulin secretion in association with a reduction in CACNA1A and intracellular calcium levels, and impaired insulin granule exocytosis in association with SYT13 down-regulation. Knockout of PAX4, CACNA1A and SYT13 reproduce the relevant phenotypes. Reduction of insulin secretion is associated with accumulation of enlarged secretory granules, and altered stoichiometry of secreted insulin to C-peptide. In HNF1A deficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of MODY3 patients, increases intracellular calcium to levels beyond those achieved by glucose, and restores C-peptide and insulin secretion to a normal stoichiometric ratio. To study HNF1A deficiency in the context of a human disease model, we also generated stem cell-derived pancreatic endocrine cells from two MODY3 patient’s induced pluripotent stem cells (iPSCs). While insulin secretion defects are constitutive in cells with complete HNF1A loss of function, β-cells heterozygous for hypomorphic HNF1A mutations are initially normal, but lose the ability to secrete insulin and acquire abnormal stoichiometric secretion ratios. Importantly, the defects observed in these stem cell models are also seen in circulating proportions of insulin:C-peptide in nine MODY3 patients.One sentence of summaryDeficiency of the transcription factor HNF1A biases islet endocrine cell fate towards α-cells, impairs intracellular calcium homeostasis and insulin exocytosis, alters the stoichiometry of insulin to C-peptide release, and leads to an accumulation of abnormal insulin secretory granules in β-cells.

Cell type-specific activation of metabolism reveals that β-cell secretion suppresses glucagon release from α-cells in rat pancreatic islets

2006 ◽  
Vol 290 (2) ◽  
pp. E308-E316 ◽  
Author(s):  
Rui Takahashi ◽  
Hisamitsu Ishihara ◽  
Akira Tamura ◽  
Suguru Yamaguchi ◽  
Takahiro Yamada ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Activation ◽  
Tricarboxylic Acid Cycle ◽  
Expression System ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Glucagon Release ◽  
Β Cells ◽  
Β Cell

Abnormal glucagon secretion is often associated with diabetes mellitus. However, the mechanisms by which nutrients modulate glucagon secretion remain poorly understood. Paracrine modulation by β- or δ-cells is among the postulated mechanisms. Herein we present further evidence of the paracrine mechanism. First, to activate cellular metabolism and thus hormone secretion in response to specific secretagogues, we engineered insulinoma INS-1E cells using an adenovirus-mediated expression system. Expression of the Na+-dependent dicarboxylate transporter (NaDC)-1 resulted in 2.5- to 4.6-fold ( P < 0.01) increases in insulin secretion in response to various tricarboxylic acid cycle intermediates. Similarly, expression of glycerol kinase (GlyK) increased insulin secretion 3.8- or 4.2-fold ( P < 0.01) in response to glycerol or dihydroxyacetone, respectively. This cell engineering method was then modified, using the Cre- loxP switching system, to activate β-cells and non-β-cells separately in rat islets. NaDC-1 expression only in non-β-cells, among which α-cells are predominant, caused an increase (by 1.8-fold, P < 0.05) in glucagon secretion in response to malate or succinate. However, the increase in glucagon release was prevented when NaDC-1 was expressed in whole islets, i.e., both β-cells and non-β-cells. Similarly, an increase in glucagon release with glycerol was observed when GlyK was expressed only in non-β-cells but not when it was expressed in whole islets. Furthermore, dicarboxylates suppressed basal glucagon secretion by 30% ( P < 0.05) when NaDC-1 was expressed only in β-cells. These data demonstrate that glucagon secretion from rat α-cells depends on β-cell activation and provide insights into the coordinated mechanisms underlying hormone secretion from pancreatic islets.

scholarly journals Mitogen-Inducible Gene 6 Triggers Apoptosis and Exacerbates ER Stress-Induced β-Cell Death

2013 ◽  
Vol 27 (1) ◽  
pp. 162-171 ◽  
Author(s):  
Yi-Chun Chen ◽  
E. Scott Colvin ◽  
Bernhard F. Maier ◽  
Raghavendra G. Mirmira ◽  
Patrick T. Fueger
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Cell Mass ◽  
Growth Factor Receptor ◽  
Protein Translation ◽  
Β Cells ◽  
Β Cell ◽  
Inducible Gene

The increased insulin secretory burden placed on pancreatic β-cells during obesity and insulin resistance can ultimately lead to β-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6+/−) to study the role of Mig6 in regulating β-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6+/− pancreatic islets was lower than wild-type islets despite having comparable β-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in β-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced β-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing β-cell survival.

scholarly journals IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tomozumi Takatani ◽  
Jun Shirakawa ◽  
Michael W. Roe ◽  
Colin A. Leech ◽  
Bernhard F. Maier ◽  
...  
Keyword(s):  
Er Stress ◽  
Protein Translation ◽  
Adaptor Proteins ◽  
Nuclear Accumulation ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Protein Instability ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Abstract Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER.

Sign in / Sign up

Export Citation Format

Share Document