Ptf1a Binds to and Activates Area III, a Highly Conserved Region of the <i>Pdx1</i> Promoter That Mediates Early Pancreas-Wide <i>Pdx1</i> Expression

Wiebe, Peter O.; Kormish, Jay D.; Roper, Venus T.; Fujitani, Yoshio; Alston, Ninche; Zaret, Kenneth S.; Wright, Christopher V.E.; Stein, Roland; Gannon, Maureen

doi:10.1128/mcb.01978-06

Cited by 81 publications

(73 citation statements)

References 59 publications

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“…Recent reports find that Ptf1a is expressed in the progenitors of pancreatic ducts, exocrine, and endocrine cells, rather than being an exocrine-specific gene as previously thought (Kawaguchi et al 2002). Thus, co-expression of PTF1a and PDX-1 is required for proper pancreatic determination and subsequent differentiation (Kawaguchi et al 2002, Afelik et al 2006, Wiebe et al 2007. IHBECs cultured for 14 days did not express PTF1a; however, all groups of cells expressed PTF1a after DM culture.…”

Section: Discussionmentioning

confidence: 83%

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells

Nagaya

Katsuta

Kaneto

et al. 2009

Journal of Endocrinology

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Transdifferentiation of cells from a patient's own liver into pancreatic b-cells could be useful for b-cell replacement. We hypothesized that intrahepatic biliary epithelial cells (IHBECs) could become a new source of insulin-producing cells. IHBECs isolated from adult mice were expanded using our novel culture method termed, collagen-embedded floating culture method (CEFCM). With CEFCM, IHBECs formed three-dimensional ductal cysts and rapidly expanded their number by about 15-fold within 2 weeks. Over 90% of cells were positive for cytokeratin 7 and 19. At day 14, IHBECs were transfected with adenoviral (Ad)-pancreas duodenum homeobox 1 (Pdx-1), NeuroD or Pdx-1/VP16. After 7 additional days in serum-and insulin-free differentiation medium (DM), cell phenotypes were determined by RT-PCR, immunostaining and ELISA for insulin. In DM control IHBECs started to express some endocrine progenitor genes (Neurog3, NeuroD, Nkx6.1, and Pdx-1) but lacked insulin gene (Ins) mRNA. Transduced expression of PDX-1, NEUROD or PDX-1/VP16 led to expression of not only INS but also GLUT2 and prohormone convertase 1 and 2. About 3% of 4000 cells counted in PDX-1/VP16 transduced cultures stained strongly for C-peptide suggesting that a subpopulation may have the capacity for differentiation.Transduced cells released insulin (Ad-PDX-1 0 . 08G0 . 05, Ad-NEUROD 0 . 33G0 . 09, Ad-PDX-1/VP16 0 . 37G 0 . 14 ng/1!10 5 cells after 48 h in culture). IHBECs can be markedly expanded, and then with molecular manipulation a subpopulation of these cells can differentiate towards a b-cell phenotype. This approach may lead to a new source of b-cells that can be used for transplantation in diabetes.

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Section: Discussionmentioning

confidence: 83%

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells

Nagaya

Katsuta

Kaneto

et al. 2009

Journal of Endocrinology

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“…In addition, adenoviral overexpression of Ptf1a, together with RBP-J, markedly increased PDX-1 expression levels in pancreatic AR42J-B13 cells, which have been reported to differentiate into insulin-producing cells [120,121]. Furthermore, it was recently demonstrated using Cre-mediated lineage tracing in mice that Area III mediates pancreas-wide PDX-1 expression during early pancreas development and that Ptf1a occupies sequences within Area III in pancreatic buds [122].…”

Section: A Variety Of Pancreatic Transcription Factors Are Involved Imentioning

confidence: 99%

Pleiotropic Roles of PDX-1 in the Pancreas

Kaneto

Miyatsuka²,

Kawamori³

et al. 2007

Rev Diabet Stud

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■ AbstractIt is well known that pancreatic and duodenal homeobox factor-1 (PDX-1) plays a pleiotropic role in the pancreas. In the developing pancreas, PDX-1 is involved in both pancreas formation and β-cell differentiation. In mature β-cells, PDX-1 transactivates insulin and other β-cell-related genes such as GLUT2 and glucokinase. Furthermore, PDX-1 plays an important role in the induction of insulin-producing cells in various non-β-cells and is thereby a possible therapeutic target for diabetes. On the other hand, under diabetic conditions, expression and/or activity of PDX-1 in β-cells is reduced, which leads to suppression of insulin biosynthesis and secretion. It is likely that PDX-1 inactivation explains, at least in part, the molecular mechanism for β-cell glucose toxicity found in diabetes.Keywords: diabetes · beta-cell differentiation · PDX-1 · pancreas development · beta-cell glucose toxicity A variety of transcription factors are involved in pancreas formation and β-cell differentiation he adult pancreas is composed of exocrine (acini and ducts) and endocrine compartments (α-, β-, δ-, ε-, and PP-cells). Each of the four endocrine cell types synthesizes and secretes one hormone: glucagon (α-cells), insulin (β-cells), somatostatin (δ-cells), ghrelin (ε-cells) and pancreatic polypeptide (PP-cells). The embryonic pancreas initially develops by fusion of the dorsal and ventral buds of the primitive gut epithelium. These two types of buds grow and fuse to form the definitive pancreas [1-4]. The thickening of the dorsal and ventral surface of the foregut is observed from E8.5-E9.5 in the mouse. It has been shown that pancreatic transcription networks play a crucial role in early pancreas organogenesis and endocrine cell formation (Figure 1) [5,6].Pancreatic and duodenal homeobox factor-1 (PDX-1) (also known as IDX-1/STF-1/IPF1) [7][8][9], a member of the large family of homeodomain (HD)-containing proteins, is expressed in precursors of the endocrine and exocrine compartments of the pancreas and is essential for pancreas development [10][11][12][13][14][15][16][17][18], β-cell differentiation [19][20][21][22][23][24][25][26][27][28][29], and maintenance of mature β-cell function by regulating several β-cell-related genes [30][31][32][33][34][35][36][37][38]. PDX-1 expression is initially observed at E8.5-E9.0 in pancreatic progenitor cells, which means that early PDX-1 expression is likely to be a useful marker of pancreatic identity. Interestingly, a study based upon temporally controlled Cre recombination demonstrated that cells expressing PDX-1 give rise to all three types of pancreatic tissue: exocrine, endocrine and duct [39,40]. Furthermore, it was shown that exocrine and endocrine progenitors express PDX-1 throughout early embryogenesis, whereas adult duct progenitors express PDX-1 only between E9.5 and

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“…While it was discovered as an activator of acinar cell-specific genes [39], at this stage it helps define exocrine, endocrine, and ductal cell types within the pancreas by binding to and activating the PDX1 promoter [40]. Shortly after the specification of the pancreatic buds, further differentiation into pancreatic endoderm (PE) and subsequent endocrine cells is initiated by the expression of NK2 homeobox 2 (NKX2.2) [41] and NK6 homeobox 1 (NKX6.1) [42].…”

Section: Primary Transitionmentioning

confidence: 99%

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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■ AbstractType 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulinproducing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development, and we summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

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Ptf1a Binds to and Activates Area III, a Highly Conserved Region of the Pdx1 Promoter That Mediates Early Pancreas-Wide Pdx1 Expression

Cited by 81 publications

References 59 publications

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells

Pleiotropic Roles of PDX-1 in the Pancreas

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

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