Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Diabetes is a disease that could be treated more effectively with a better understanding of pancreas development. This review examines the role of master regulator genes driving crucial steps in pancreas development, from foregut specification to differentiation of the five endocrine cell types. The roles of Pdx1, Ptf1a, and Ngn3 are particularly examined as they are both necessary and sufficient for promoting pancreatic cell fates (Pdx1, Ptf1a) and endocrine cell development (Ngn3). The roles of Arx and Pax4 are studied as they compose part of the regulatory mechanism balancing development of different types of endocrine cells within the iselts and promote the development of alpha/PP and beta/delta cell progenitors, respectively. The roles of the aforementioned genes, and the consequences of misexpression of them for functionality of the pancreas, are examined through recent studies in model organisms, particularly Xenopus and zebrafish. Recent developments in cell replacement therapy research are also covered, concentrating on stem cell research (coaxing both adult and embryonic stem cells toward a beta cell fate) and transdifferentiation (generating beta cells from other differentiated cell types).
Fig. 1. From pre-pancreatic endoderm to pancreas. A schematic diagram outlining the major developmental steps involved increating different pancreatic cell types. Important progenitors are included along with genes important in key steps inpancreas development.
Fig. 2. Creating a new pancreas, the future of diabetestherapy. Many future diabetes therapies revolve around theidea of creating new pancreas cells. There are two majorways to do this. Transdifferentiation involves changinga differentiated cell type into b cells by turning on pancreatictranscription factors in non-b cells. The other method isguiding stem cells (either from adult or embryonic tissue) tobecome pancreatic b cells using combinations of growthfactors and chemicals. ES cells, embryonic stem cells; EGF,epidermal growth factor; LIF, leukemia inhibitory factor.
Afelik,
Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue.
2006, Pubmed,
Xenbase
Afelik,
Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue.
2006,
Pubmed
,
Xenbase Ahlgren,
The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice.
1996,
Pubmed Ai,
Human marrow-derived mesodermal progenitor cells generate insulin-secreting islet-like clusters in vivo.
2007,
Pubmed Ait-Lounis,
Novel function of the ciliogenic transcription factor RFX3 in development of the endocrine pancreas.
2007,
Pubmed Apelqvist,
Notch signalling controls pancreatic cell differentiation.
1999,
Pubmed
,
Xenbase Bajada,
Updates on stem cells and their applications in regenerative medicine.
2008,
Pubmed Banting,
Pancreatic Extracts in the Treatment of Diabetes Mellitus.
1922,
Pubmed Blitz,
Germ layers to organs: using Xenopus to study "later" development.
2006,
Pubmed
,
Xenbase Bonner-Weir,
Transdifferentiation of pancreatic ductal cells to endocrine beta-cells.
2008,
Pubmed Burlison,
Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells.
2008,
Pubmed Cano,
Pancreatic development and disease.
2007,
Pubmed Chen,
Retinoic acid signaling is essential for pancreas development and promotes endocrine at the expense of exocrine cell differentiation in Xenopus.
2004,
Pubmed
,
Xenbase Chung,
Intra-endodermal interactions are required for pancreatic beta cell induction.
2008,
Pubmed Collombat,
Opposing actions of Arx and Pax4 in endocrine pancreas development.
2003,
Pubmed Collombat,
The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas.
2005,
Pubmed Collombat,
Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression.
2007,
Pubmed Collombat,
Specifying pancreatic endocrine cell fates.
2006,
Pubmed D'Amour,
Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.
2006,
Pubmed diIorio,
Sonic hedgehog is required early in pancreatic islet development.
2002,
Pubmed Esni,
Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas.
2004,
Pubmed Field,
Formation of the digestive system in zebrafish. II. Pancreas morphogenesis.
2003,
Pubmed Fodor,
Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach.
2007,
Pubmed Fukuda,
Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas.
2006,
Pubmed Gangaram-Panday,
Towards stem-cell therapy in the endocrine pancreas.
2007,
Pubmed Gao,
In vitro cultivation of islet-like cell clusters from human umbilical cord blood-derived mesenchymal stem cells.
2008,
Pubmed Gao,
Transplantation of bone marrow derived cells promotes pancreatic islet repair in diabetic mice.
2008,
Pubmed Gierl,
The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells.
2006,
Pubmed Gradwohl,
neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas.
2000,
Pubmed
,
Xenbase Gu,
Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
2002,
Pubmed Hebrok,
Notochord repression of endodermal Sonic hedgehog permits pancreas development.
1998,
Pubmed Hebrok,
Hedgehog signaling in pancreas development.
2003,
Pubmed Heller,
Genetic determinants of pancreatic epsilon-cell development.
2005,
Pubmed Hess,
Bone marrow-derived stem cells initiate pancreatic regeneration.
2003,
Pubmed Horb,
Experimental conversion of liver to pancreas.
2003,
Pubmed
,
Xenbase Jacquemin,
Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3.
2000,
Pubmed Jacquemin,
The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade.
2003,
Pubmed Jarikji,
Differential ability of Ptf1a and Ptf1a-VP16 to convert stomach, duodenum and liver to pancreas.
2007,
Pubmed
,
Xenbase Jensen,
Gene regulatory factors in pancreatic development.
2004,
Pubmed Johansson,
Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types.
2007,
Pubmed Jonsson,
Insulin-promoter-factor 1 is required for pancreas development in mice.
1994,
Pubmed Jørgensen,
An illustrated review of early pancreas development in the mouse.
2007,
Pubmed Jun,
Regeneration of pancreatic beta cells.
2008,
Pubmed Karnieli,
Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation.
2007,
Pubmed Kawaguchi,
The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors.
2002,
Pubmed Kelly,
Development of the pancreas in Xenopus laevis.
2000,
Pubmed
,
Xenbase Krapp,
The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas.
1998,
Pubmed Lee,
Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.
2006,
Pubmed Lee,
Cellular therapies for type 1 diabetes.
2008,
Pubmed Leonard,
Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells.
1993,
Pubmed Limbert,
Beta-cell replacement and regeneration: Strategies of cell-based therapy for type 1 diabetes mellitus.
2008,
Pubmed Lin,
Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas.
2004,
Pubmed Lü,
Stem cells therapy for type 1 diabetes.
2007,
Pubmed Lynn,
Sox9 coordinates a transcriptional network in pancreatic progenitor cells.
2007,
Pubmed Madsen,
Towards cell therapy for diabetes.
2006,
Pubmed Madsen,
Stem cells and diabetes treatment.
2005,
Pubmed Martín,
Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice.
2005,
Pubmed Masui,
Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex.
2007,
Pubmed McLin,
Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development.
2007,
Pubmed
,
Xenbase Meivar-Levy,
Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta.
2007,
Pubmed Mellitzer,
IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas.
2006,
Pubmed Miller,
IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene.
1994,
Pubmed
,
Xenbase Minami,
Pancreatic acinar-to-beta cell transdifferentiation in vitro.
2008,
Pubmed Miyatsuka,
Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.
2006,
Pubmed Molotkov,
Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development.
2005,
Pubmed Moriya,
In vitro pancreas formation from Xenopus ectoderm treated with activin and retinoic acid.
2000,
Pubmed
,
Xenbase Murtaugh,
Pancreas and beta-cell development: from the actual to the possible.
2007,
Pubmed Ober,
From endoderm formation to liver and pancreas development in zebrafish.
2003,
Pubmed Offield,
PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
1996,
Pubmed
,
Xenbase Ohlsson,
IPF1, a homeodomain-containing transactivator of the insulin gene.
1993,
Pubmed Pan,
Retinoic acid-mediated patterning of the pre-pancreatic endoderm in Xenopus operates via direct and indirect mechanisms.
2007,
Pubmed
,
Xenbase Peshavaria,
XIHbox 8, an endoderm-specific Xenopus homeodomain protein, is closely related to a mammalian insulin gene transcription factor.
1994,
Pubmed
,
Xenbase Phillips,
Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage.
2007,
Pubmed Polak,
Early pattern of differentiation in the human pancreas.
2000,
Pubmed Prado,
Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development.
2004,
Pubmed Robertson,
The spleen--a potential source of new islets for transplantation?
2008,
Pubmed Roy,
Hedgehog signaling pathway is essential for pancreas specification in the zebrafish embryo.
2001,
Pubmed Schwitzgebel,
Expression of neurogenin3 reveals an islet cell precursor population in the pancreas.
2000,
Pubmed Schwitzgebel,
Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.
2003,
Pubmed Sellick,
Mutations in PTF1A cause pancreatic and cerebellar agenesis.
2004,
Pubmed Seymour,
SOX9 is required for maintenance of the pancreatic progenitor cell pool.
2007,
Pubmed Shternhall-Ron,
Ectopic PDX-1 expression in liver ameliorates type 1 diabetes.
2007,
Pubmed Slack,
Transdifferentiation and metaplasia--switching cell types.
2001,
Pubmed Sosa-Pineda,
The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas.
1997,
Pubmed Spagnoli,
The Gata5 target, TGIF2, defines the pancreatic region by modulating BMP signals within the endoderm.
2008,
Pubmed
,
Xenbase Stafford,
A conserved role for retinoid signaling in vertebrate pancreas development.
2004,
Pubmed
,
Xenbase Stoffers,
Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.
1997,
Pubmed Tang,
Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation.
2006,
Pubmed Tang,
Reprogramming liver-stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors.
2006,
Pubmed Tosh,
How cells change their phenotype.
2002,
Pubmed van den Brink,
Hedgehog signaling in development and homeostasis of the gastrointestinal tract.
2007,
Pubmed Wang,
Ghrelin is a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum.
2008,
Pubmed Wiebe,
Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression.
2007,
Pubmed Wierup,
The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas.
2002,
Pubmed Wilson,
Gene expression cascades in pancreatic development.
2003,
Pubmed Wright,
XlHbox 8: a novel Xenopus homeo protein restricted to a narrow band of endoderm.
1989,
Pubmed
,
Xenbase Yee,
Zebrafish pdx1 morphant displays defects in pancreas development and digestive organ chirality, and potentially identifies a multipotent pancreas progenitor cell.
2001,
Pubmed Zecchin,
Evolutionary conserved role of ptf1a in the specification of exocrine pancreatic fates.
2004,
Pubmed Zhang,
Downregulation of Hedgehog signaling is required for organogenesis of the small intestine in Xenopus.
2001,
Pubmed
,
Xenbase
