Talk:Endocrine - Pancreas Development

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Cite this page: Hill, M.A. (2019, October 24) Embryology Endocrine - Pancreas Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Endocrine_-_Pancreas_Development

2018

Neurog3 misexpression unravels mouse pancreatic ductal cell plasticity

PLoS One. 2018 Aug 9;13(8):e0201536. doi: 10.1371/journal.pone.0201536. eCollection 2018.

Vieira A1, Vergoni B1, Courtney M1, Druelle N1, Gjernes E1, Hadzic B1, Avolio F1, Napolitano T1, Navarro Sanz S1, Mansouri A2,3, Collombat P1.

Abstract

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. PMID: 30092080 PMCID: PMC6084906 DOI: 10.1371/journal.pone.0201536


Comparison of enteroendocrine cells and pancreatic β-cells using gene expression profiling and insulin gene methylation

PLoS One. 2018 Oct 31;13(10):e0206401. doi: 10.1371/journal.pone.0206401. eCollection 2018.

Ryu GR1, Lee E1, Kim JJ1, Moon SD1, Ko SH1, Ahn YB1, Song KH1.

Abstract

Various subtypes of enteroendocrine cells (EECs) are present in the gut epithelium. EECs and pancreatic β-cells share similar pathways of differentiation during embryonic development and after birth. In this study, similarities between EECs and β-cells were evaluated in detail. To obtain specific subtypes of EECs, cell sorting by flow cytometry was conducted from STC-1 cells (a heterogenous EEC line), and each single cell was cultured and passaged. Five EEC subtypes were established according to hormone expression, measured by quantitative RT-PCR and immunostaining: L, K, I, G and S cells expressing glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, cholecystokinin, gastrin and secretin, respectively. Each EEC subtype was found to express not only the corresponding gut hormone but also other gut hormones. Global microarray gene expression profiles revealed a higher similarity between each EEC subtype and MIN6 cells (a β-cell line) than between C2C12 cells (a myoblast cell line) and MIN6 cells, and all EEC subtypes were highly similar to each other. Genes for insulin secretion-related proteins were mostly enriched in EECs. However, gene expression of transcription factors crucial in mature β-cells, such as PDX1, MAFA and NKX6.1, were remarkably low in all EEC subtypes. Each EEC subtype showed variable methylation in three cytosine-guanosine dinucleotide sites in the insulin gene (Ins2) promoter, which were fully unmethylated in MIN6 cells. In conclusion, our data confirm that five EEC subtypes are closely related to β-cells, suggesting a potential target for cell-based therapy in type 1 diabetes. PMID: 30379923 PMCID: PMC6209304 DOI: 10.1371/journal.pone.0206401

Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis

Nat Commun. 2018 Aug 22;9(1):3356. doi: 10.1038/s41467-018-05740-1.

Scavuzzo MA1, Hill MC1, Chmielowiec J2,3,4, Yang D4, Teaw J2,3,4, Sheng K5,6,7, Kong Y8, Bettini M8,9, Zong C6,7,9, Martin JF10,11,12,13, Borowiak M14,15,16,17,18,19.

Abstract

Decoding the molecular composition of individual Ngn3 + endocrine progenitors (EPs) during pancreatic morphogenesis could provide insight into the mechanisms regulating hormonal cell fate. Here, we identify population markers and extensive cellular diversity including four EP subtypes reflecting EP maturation using high-resolution single-cell RNA-sequencing of the e14.5 and e16.5 mouse pancreas. While e14.5 and e16.5 EPs are constantly born and share select genes, these EPs are overall transcriptionally distinct concomitant with changes in the underlying epithelium. As a consequence, e16.5 EPs are not the same as e14.5 EPs: e16.5 EPs have a higher propensity to form beta cells. Analysis of e14.5 and e16.5 EP chromatin states reveals temporal shifts, with enrichment of beta cell motifs in accessible regions at later stages. Finally, we provide transcriptional maps outlining the route progenitors take as they make cell fate decisions, which can be applied to advance the in vitro generation of beta cells. PMID: 30135482 PMCID: PMC6105717

2016

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

Genes Dev. 2016 Aug 15;30(16):1852-65. doi: 10.1101/gad.284729.116. Epub 2016 Sep 1.

Bechard ME1, Bankaitis ED1, Hipkens SB2, Ustione A3, Piston DW3, Yang YP1, Magnuson MA2, Wright CV1.

Abstract

The current model for endocrine cell specification in the pancreas invokes high-level production of the transcription factor Neurogenin 3 (Neurog3) in Sox9(+) bipotent epithelial cells as the trigger for endocrine commitment, cell cycle exit, and rapid delamination toward proto-islet clusters. This model posits a transient Neurog3 expression state and short epithelial residence period. We show, however, that a Neurog3(TA.LO) cell population, defined as Neurog3 transcriptionally active and Sox9(+) and often containing nonimmunodetectable Neurog3 protein, has a relatively high mitotic index and prolonged epithelial residency. We propose that this endocrine-biased mitotic progenitor state is functionally separated from a pro-ductal pool and endows them with long-term capacity to make endocrine fate-directed progeny. A novel BAC transgenic Neurog3 reporter detected two types of mitotic behavior in Sox9(+) Neurog3(TA.LO) progenitors, associated with progenitor pool maintenance or derivation of endocrine-committed Neurog3(HI) cells, respectively. Moreover, limiting Neurog3 expression dramatically increased the proportional representation of Sox9(+) Neurog3(TA.LO) progenitors, with a doubling of its mitotic index relative to normal Neurog3 expression, suggesting that low Neurog3 expression is a defining feature of this cycling endocrine-biased state. We propose that Sox9(+) Neurog3(TA.LO) endocrine-biased progenitors feed production of Neurog3(HI) endocrine-committed cells during pancreas organogenesis. © 2016 Bechard et al.; Published by Cold Spring Harbor Laboratory Press. KEYWORDS: Neurog3; endocrine-biased; mitotic; progenitor

PMID 27585590 PMCID: PMC5024683 DOI: 10.1101/gad.284729.116

Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice

Nat Med. 2016 Mar;22(3):306-11. doi: 10.1038/nm.4030. Epub 2016 Jan 25.

Vegas AJ1,2, Veiseh O1,2,3, Gürtler M4, Millman JR4, Pagliuca FW4, Bader AR1,2, Doloff JC1,2, Li J1,2, Chen M1,2, Olejnik K1,2, Tam HH1,2,3, Jhunjhunwala S1,2, Langan E1,2, Aresta-Dasilva S1,2, Gandham S1,2, McGarrigle JJ5, Bochenek MA5, Hollister-Lock J6, Oberholzer J5, Greiner DL7, Weir GC6, Melton DA4,8, Langer R1,2,3,9,10, Anderson DG1,2,3,9,10.

Abstract

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

PMID 26808346

2014

Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas

PLoS One. 2013 Aug 5;8(8):e70397. doi: 10.1371/journal.pone.0070397. Print 2013.

Suissa Y1, Magenheim J, Stolovich-Rain M, Hija A, Collombat P, Mansouri A, Sussel L, Sosa-Pineda B, McCracken K, Wells JM, Heller RS, Dor Y, Glaser B.

Abstract

Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin(+) cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin(+) cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin(+) cells do not express any other islet hormone. Pancreatic gastrin(+) cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3(+) endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin(+) cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells.

PMID 23940571

2013

Development of the human pancreas from foregut to endocrine commitment

Diabetes. 2013 Oct;62(10):3514-22. doi: 10.2337/db12-1479. Epub 2013 Apr 29.

Jennings RE1, Berry AA, Kirkwood-Wilson R, Roberts NA, Hearn T, Salisbury RJ, Blaylock J, Piper Hanley K, Hanley NA. Author information Abstract Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation toward a β-cell fate. However, almost no information exists on the early events of human pancreatic specification in the distal foregut, bud formation, and early development. Here, we have studied the expression profiles of key lineage-specific markers to understand differentiation and morphogenetic events during human pancreas development. The notochord was adjacent to the dorsal foregut endoderm during the fourth week of development before pancreatic duodenal homeobox-1 detection. In contrast to the published data from mouse embryos, during human pancreas development, we detected only a single-phase of Neurogenin 3 (NEUROG3) expression and endocrine differentiation from approximately 8 weeks, before which Nirenberg and Kim homeobox 2.2 (NKX2.2) was not observed in the pancreatic progenitor cell population. In addition to revealing a number of disparities in timing between human and mouse development, these data, directly assembled from human tissue, allow combinations of transcription factors to define sequential stages and differentiating pancreatic cell types. The data are anticipated to provide a useful reference point for stem cell researchers looking to differentiate human PSCs in vitro toward the pancreatic β-cell so as to model human development or enable drug discovery and potential cell therapy. PMID: 23630303 PMCID: PMC3781486 DOI: 10.2337/db12-1479

Bioluminescence Imaging of β Cells and Intrahepatic Insulin Gene Activity under Normal and Pathological Conditions

PLoS One. 2013 Apr 4;8(4):e60411. doi: 10.1371/journal.pone.0060411. Print 2013.

Katsumata T, Oishi H, Sekiguchi Y, Nagasaki H, Daassi D, Tai PH, Ema M, Kudo T, Takahashi S. Source Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.

Abstract

In diabetes research, bioluminescence imaging (BLI) has been applied in studies of β-cell impairment, development, and islet transplantation. To develop a mouse model that enables noninvasive imaging of β cells, we generated a bacterial artificial chromosome (BAC) transgenic mouse in which a mouse 200-kbp genomic fragment comprising the insulin I gene drives luciferase expression (Ins1-luc BAC transgenic mouse). BLI of mice was performed using the IVIS Spectrum system after intraperitoneal injection of luciferin, and the bioluminescence signal from the pancreatic region analyzed. When compared with MIP-Luc-VU mice [FVB/N-Tg(Ins1-luc)VUPwrs/J] expressing luciferase under the control of the 9.2-kbp mouse insulin I promoter (MIP), the bioluminescence emission from Ins1-luc BAC transgenic mice was enhanced approximately 4-fold. Streptozotocin-treated Ins1-luc BAC transgenic mice developed severe diabetes concomitant with a sharp decline in the BLI signal intensity in the pancreas. Conversely, mice fed a high-fat diet for 8 weeks showed an increase in the signal, reflecting a decrease or increase in the β-cell mass. Although the bioluminescence intensity of the islets correlated well with the number of isolated islets in vitro, the intensity obtained from a living mouse in vivo did not necessarily reflect an absolute quantification of the β-cell mass under pathological conditions. On the other hand, adenovirus-mediated gene transduction of β-cell-related transcription factors in Ins1-luc BAC transgenic mice generated luminescence from the hepatic region for more than 1 week. These results demonstrate that BLI in Ins1-luc BAC transgenic mice provides a noninvasive method of imaging islet β cells and extrapancreatic activity of the insulin gene in the liver under normal and pathological conditions. PMID 23593212

2012

Metabolic manifestations of insulin deficiency do not occur without glucagon action

Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14972-6. Epub 2012 Aug 13.

Lee Y, Berglund ED, Wang MY, Fu X, Yu X, Charron MJ, Burgess SC, Unger RH. Source Touchstone Center for Diabetes Research, Hypothalamic Research Center, Department of Internal Medicine, and Advanced Imaging Research Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Abstract

To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR(-/-)) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR(-/-) mice with similar β-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.

PMID 22891336


2011

Pancreas organogenesis: from bud to plexus to gland

Dev Dyn. 2011 Mar;240(3):530-65. doi: 10.1002/dvdy.22584. Pan FC, Wright C.

Abstract

Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature β-cells. Copyright © 2011 Wiley-Liss, Inc.

PMID 21337462

Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

Proc Natl Acad Sci U S A. 2011 Nov 14. [Epub ahead of print]

Rovira M, Huang W, Yusuff S, Shim JS, Ferrante AA, Liu JO, Parsons MJ. Source Departments of Surgery, Pharmacology and Molecular Sciences, and Department of Oncology, and McKusick-Nathans Institute for Genetic Medicine, The Johns Hopkins University, Baltimore, MD 21205.

Abstract

Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.

PMID 22084084

http://www.pnas.org/content/108/48/19264.abstract?etoc Proc Natl Acad Sci U S A.

Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development

PLoS One. 2011;6(11):e27879. Epub 2011 Nov 17.

Xia F, Dohi T, Martin NM, Raskett CM, Liu Q, Altieri DC. Source Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.

Abstract

The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin(+) β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo.

PMID 22114719

Early-life origins of type 2 diabetes: fetal programming of the Beta-cell mass

Exp Diabetes Res. 2011;2011:105076. Epub 2011 Oct 24.

Portha B, Chavey A, Movassat J. Source Université Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), EAC 4413 Centre National de la Recherche Scientifique, 75205 Paris, France.

Abstract

A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

PMID 22110471

Pancreatic mesenchyme regulates epithelial organogenesis throughout development

PLoS Biol. 2011 Sep;9(9):e1001143. Epub 2011 Sep 6.

Landsman L, Nijagal A, Whitchurch TJ, Vanderlaan RL, Zimmer WE, Mackenzie TC, Hebrok M. Source Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.

Abstract

The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator of this process. These results have implications for developing strategies to expand pancreas progenitors and β-cells for clinical transplantation.

PMID 21909240

http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001143

2010

Elevated glucose induces congenital heart defects by altering the expression of tbx5, tbx20, and has2 in developing zebrafish embryos

Liang J, Gui Y, Wang W, Gao S, Li J, Song H. Birth Defects Res A Clin Mol Teratol. 2010 Jun;88(6):480-6.

BACKGROUND: Maternal diabetes increases the risk of congenital heart defects in infants, and hyperglycemia acts as a major teratogen. Multiple steps of cardiac development, including endocardial cushion morphogenesis and development of neural crest cells, are challenged under elevated glucose conditions. However, the direct effect of hyperglycemia on embryo heart organogenesis remains to be investigated.

METHODS: Zebrafish embryos in different stages were exposed to D-glucose for 12 or 24 hr to determine the sensitive window during early heart development. In the subsequent study, 6 hr post-fertilization embryos were treated with either 25 mmol/liter D-glucose or L-glucose for 24 hr. The expression of genes was analyzed by whole-mount in situ hybridization.

RESULTS: The highest incidence of cardiac malformations was found during 6-30 hpf exposure periods. After 24 hr exposure, D-glucose-treated embryos exhibited significant developmental delay and diverse cardiac malformations, but embryos exposed to L-glucose showed no apparent phenotype. Further investigation of the origin of heart defects showed that cardiac looping was affected earliest, while the specification of cardiac progenitors and heart tube assembly were complete. Moreover, the expression patterns of tbx5, tbx20, and has2 were altered in the defective hearts.

CONCLUSIONS: Our data demonstrate that elevated glucose alone induces cardiac defects in zebrafish embryos by altering the expression pattern of tbx5, tbx20, and has2 in the heart. We also show the first evidence that cardiac looping is affected earliest during heart organogenesis. These research results are important for devising preventive and therapeutic strategies aimed at reducing the occurrence of congenital heart defects in diabetic pregnancy.

PMID: 20306498 http://www.ncbi.nlm.nih.gov/pubmed/20306498

Fetal topographical anatomy of the pancreatic head and duodenum with special reference to courses of the pancreaticoduodenal arteries

Jin ZW, Yu HC, Cho BH, Kim HT, Kimura W, Fujimiya M, Murakami G. Yonsei Med J. 2010 May;51(3):398-406.

PURPOSE: The purpose of this study is to provide better understanding as to how the "double" vascular arcades, in contrast to other intestinal marginal vessels, develop along the right margin of the pancreatic head. MATERIALS AND METHODS: In human fetuses between 8-30 weeks, we described the topographical anatomy of the vessels, bile duct, duodenum as well as the ventral and dorsal primordia of the pancreatic head with an aid of pancreatic polypeptide immunohisto-chemistry. RESULTS: The contents of the hepatoduodenal ligament crossed the superior side of the pylorus. Moreover, the right hepatic artery originating from the superior mesenteric artery ran along the superior aspect of the pancreatic head. An arterial arcade, corresponding to the posterior pancreaticoduodenal arteries, encircled the superior part of the pancreatic head, whereas another arcade, corresponding to the anterior pancreaticoduodenal arteries, surrounded the inferior part. The dorsal promordium of the pancreas surrounded and/or mixed the ventral primordium at 13-16 weeks. Thus, both arterial arcades were likely to attach to the dorsal primordium. CONCLUSION: The fetal anatomy of the pancreaticoduodenal vascular arcades as well as that of the hepatoduodenal ligament were quite different from adults in topographical relations. Thus, in the stage later than 30 weeks, further rotation of the duodenum along a horizontal axis seemed to be required to move the pylorus posterosuperiorly and to reflect the superior surface of the pancreatic head posteriorly. However, to change the topographical anatomy of the superior and inferior arterial arcades into the final position, re-arrangement of the pancreatic parenchyma might be necessary in the head.

PMID: 20376893 http://www.ncbi.nlm.nih.gov/pubmed/20376893

http://www.eymj.org/search.php?where=aview&id=128080&code=0069YMJ&vmode=AFTR

Wolcott-Rallison syndrome

Orphanet J Rare Dis. 2010 Nov 4;5:29.

Julier C, Nicolino M.

Inserm UMR-S 958, Faculté de Médecine Denis-Diderot, Paris, France. cecile.julier@inserm.fr

Abstract Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

PMID: 21050479

2009

Remodelling sympathetic innervation in rat pancreatic islets ontogeny

Cabrera-Vásquez S, Navarro-Tableros V, Sánchez-Soto C, Gutiérrez-Ospina G, Hiriart M. BMC Dev Biol. 2009 Jun 17;9:34. PMID: 19534767

http://www.ncbi.nlm.nih.gov/pubmed/19534767

"Adult pancreatic β cells secrete insulin in response to an increase in extracellular glucose. At birth, this response is not fully developed as neonate β-cells are insensitive to glucose and synthesize and secrete less insulin than adults [1]. Pancreatic islets are innervated by autonomic fibres. In particular, sympathetic neural cell bodies are located in the superior mesenteric and celiac ganglia and are components of the splanchnic nerve and parasympathetic innervation comes from the vagus nerve [2]."

Conclusion The results suggest that NGF signalling play an important role in the guidance of blood vessels and sympathetic fibres toward the islets during foetal and neonatal stages and could also preserve innervation at later stages of life.


1. Navarro-Tableros V, Fiordelisio T, Hernandez-Cruz A, Hiriart M: Physiological development of insulin secretion, calcium channels, and GLUT2 expression of pancreatic rat beta-cells. Am J Physiol Endocrinol Metab 2007, 292(4):E1018-1029.

2. Salvioli B, Bovara M, Barbara G, De Ponti F, Stanghellini V, Tonini M, Guerrini S, Cremon C, Degli Esposti M, Koumandou M, et al.: Neurology and neuropathology of the pancreatic innervation. Jop 2002, 3(2):26-33


Islet architecture: A comparative study

Islets. 2009 Sep-Oct;1(2):129-36.

Kim A, Miller K, Jo J, Kilimnik G, Wojcik P, Hara M. Source Department of Medicine, The University of Chicago, Chicago, IL, USA.

Abstract

Emerging reports on the organization of the different hormone-secreting cell types (alpha, glucagon; beta, insulin; and delta, somatostatin) in human islets have emphasized the distinct differences between human and mouse islets, raising questions about the relevance of studies of mouse islets to human islet physiology. Here, we examine the differences and similarities between the architecture of human and mouse islets. We studied islets from various mouse models including ob/ob and db/db and pregnant mice. We also examined the islets of monkeys, pigs, rabbits and birds for further comparisons. Despite differences in overall body and pancreas size as well as total beta-cell mass among these species, the distribution of their islet sizes closely overlaps, except in the bird pancreas in which the delta-cell population predominates (both in singlets and clusters) along with a small number of islets. Markedly large islets (>10,000 mum(2)) were observed in human and monkey islets as well as in islets from ob/ob and pregnant mice. The fraction of alpha-, beta- and delta-cells within an islet varied between islets in all the species examined. Furthermore, there was variability in the distribution of alpha- and delta-cells within the same species. In summary, human and mouse islets share common architectural features that may reflect demand for insulin. Comparative studies of islet architecture may lead to a better understanding of islet development and function.

PMID: 20606719

Islet size and β-cell ratio for different species

The following species comparison table has been slightly modified from Table 1 data in a recent paper by Kim etal., 2009.[1] Islet size is described as an effective diameter of a circle, which depicts the same area as a measured islet area. β-cell ratio is the area ratio of β-cells in an islet. Both data sets are expressed as the mean value with its standard deviation.

Species Age Islet size (μm) β-cell ratio
Human 39 years (adult) 50 ± 29 0.64 ± 0.21
Monkey 1 year 67 ± 38* 0.79 ± 0.14*
Pig 6 month 49 ± 15a 0.89 ± 0.11*
Rabbit 6 month 64 ± 28* 0.79 ± 0.17*
Bird 40 day 24 ± 6* 0.46 ± 0.24*
Wild-type mouse 6 month 116 ± 80* 0.85 ± 0.14*
Pregnant mouse 3 month 112 ± 94* 0.84 ± 0.22*
ob/ob mouse 15 week 86 ± 76* 0.92 ± 0.11*
db/db mouse 15 week 47 ± 24b 0.53 ± 0.24c

*p < 0.0001 compared with human.

ap = 0.65

bp = 0.42

cp = 0.0004

Reference

  1. <pubmed>20606719</pubmed>

2005

Wnt5 signaling in vertebrate pancreas development

BMC Biol. 2005 Oct 24;3:23.

Kim HJ, Schleiffarth JR, Jessurun J, Sumanas S, Petryk A, Lin S, Ekker SC. Source Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA. kimx0183@umn.edu Abstract BACKGROUND: Signaling by the Wnt family of secreted glycoproteins through their receptors, the frizzled (Fz) family of seven-pass transmembrane proteins, is critical for numerous cell fate and tissue polarity decisions during development.

RESULTS: We report a novel role of Wnt signaling in organogenesis using the formation of the islet during pancreatic development as a model tissue. We used the advantages of the zebrafish to visualize and document this process in living embryos and demonstrated that insulin-positive cells actively migrate to form an islet. We used morpholinos (MOs), sequence-specific translational inhibitors, and time-lapse imaging analysis to show that the Wnt-5 ligand and the Fz-2 receptor are required for proper insulin-cell migration in zebrafish. Histological analyses of islets in Wnt5a(-/-) mouse embryos showed that Wnt5a signaling is also critical for murine pancreatic insulin-cell migration.

CONCLUSION: Our results implicate a conserved role of a Wnt5/Fz2 signaling pathway in islet formation during pancreatic development. This study opens the door for further investigation into a role of Wnt signaling in vertebrate organ development and disease.

PMID 16246260