Minireview: Transcriptional Regulation in Pancreatic Development

Habener, Joel F.; Kemp, D. S.; Thomas, Melissa K.

doi:10.1210/en.2004-1576

Cited by 359 publications

(350 citation statements)

References 109 publications

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“…Upregulation of the NGN3 and NKX6-1 cell populations also occurred following FOXO1 gene knockdown in the islets, while there was no change in the abundance of other transcription factors critical for pancreatic islet cell differentiation, including ISL1, NKX2-2 and PAX6 [2]. These results are supported by our previous finding of a parallel decrease in NGN3 and NKX6-1 expression from 8-21 weeks of human fetal pancreatic development while ISL1, NKX2-2 and PAX6 increased significantly [18].…”

Section: Discussionmentioning

confidence: 97%

“…Determining the factors which regulate development of the human pancreas and maintain survival and function of islets may help devise cell-based strategies for diabetes treatment. One such research focus is aimed at better understanding the role of transcription factor cascades [2]. Several studies have suggested that the forkhead box (FOXO) transcription factors are key regulators of pancreatic beta cell function.…”

Section: Introductionmentioning

confidence: 99%

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Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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Aims/hypothesis Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. Methods Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). Results Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19) + (p<0.01) and insulin + cells (p<0.05) in parallel with increased phospho-Akt (p<0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3 + (p<0.01) and NK6 homeobox 1 (NKX6-1) + (p<0.05) cells in parallel with increases in insulin gene expression (p<0.03) and C-peptide + cells (p<0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p<0.01). Conclusions/interpretation Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.Keywords Human fetal pancreas . Human islet epithelial cell clusters . Islet transcription factors . Nuclear FOXO1 . FOXO1 siRNA Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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“…During pancreatic differentiation, neurog3 mRNA has been detected in pancreatic buds as early as embryonic day (E) 9.5 [13] and the neurog3 protein has been found at E11.5 in epithelial cells of the pancreatic buds [14]. Similar expression patterns were described for Pax6 and Isl1 ( [13], for review see [15]). In parallel, during neuronal and glial cell development, Isl1, Pax6, and neurog3 mRNA and proteins could be detected as early as E10.5, when neurogenesis begins ( [16,17], see Table 1).…”

Section: Neuronal Vs Pancreatic Differentiation In Vivo and Of Es Celmentioning

confidence: 91%

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

2006

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Abbreviations E embryonal day EB embryoid body EMT epithelial-mesenchymal transition ES embryonic stemThe generation of insulin-producing cells from differentiating mouse embryonic stem (ES) cells was described some years ago [1], but subsequent studies could not replicate the results. Instead, using the same differentiation protocol, it was found that insulin immunoreactivity occurred as a consequence of insulin uptake from the medium [2], neuronal cells were formed [2-4], or insulin was released as an artefact from differentiated ES cells [2,3]. Functional pancreatic cells, however, were successfully generated using lineage selection strategies based on pancreas-specific promoters [5,6], by modified protocols in combination with transgene expression [7][8][9], or by addition of a phosphoinositol-3 kinase inhibitor [10]. The differentiated cells showed properties of (neonatal) beta cells, such as insulin transcripts and C-peptide/insulin co-expression, insulin-secretory granules, ion channel activity of embryonal beta cells, and normalisation of blood glucose level after transplantation into diabetic mice [5][6][7][8][9][10]. Most of the differentiation protocols required a long cultivation period, including 4-5 days of embryoid body (EB) formation, followed by 3-4 weeks of differentiation, and some protocols required genetic manipulation. Recently, a relatively short procedure of pancreatic differentiation by a three-step experimental approach was published [11]. The strategy is based on the combined treatment by activin A, all-trans-retinoic acid, and other factors such as basic fibroblast growth factor (bFGF), which induced murine ES cells to differentiate into insulin-producing cells within 2 weeks. The authors presented results on insulin transcripts, C-peptide/insulin co-expression, glucose-induced insulin release, and the normalisation of glycaemia following transplantation into diabetic mice. Neuronal vs pancreatic differentiation in vivo and of ES cells in vitroOn looking more closely at the C-peptide-positive cells differentiated according to the protocol of Shi et al. [11], it became obvious that both pancreatic and neuronal differentiation had been induced. In part, the clusters showed the typical morphology of grape-like structures, but also neuronal cell types (Fig. 1a). Immunohistochemical stainings revealed varying levels of co-expression of C-peptide, a byproduct of pro-insulin synthesis (used as a marker for insulin-producing cells), and the neuron-specific beta-III tubulin (Fig. 1b-g). Such ectoderm-derived insulin-producing (C-peptide-positive) cells have been generated from ES cells via EB formation, as well as from monolayer cultures

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“…PDX-1 has two critical roles, first in the early development of both the endocrine and exocrine pancreas, and then in the later differentiation of the b-cell (reviewed in [1,2]). Mice and humans deficient for Pdx1 have pancreatic agenesis.…”

Section: Introductionmentioning

confidence: 99%

Two conserved domains in PCIF1 mediate interaction with pancreatic transcription factor PDX‐1

Liu

Oliver‐Krasinski

2006

FEBS Letters

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PCIF1 is a TRAF and POZ domain containing nuclear factor that interacts with and inhibits transactivation of pancreatic homeodomain transcription factor PDX-1. Here, we demonstrate interaction of endogenous PDX-1 and PCIF1 in MIN6 insulinoma cells. Within PCIF1, the TRAF and POZ domains are both required for physical and functional interaction with the C-terminus of PDX-1, whereas the C-terminal domain of PCIF1 directs its nuclear localization. A human PDX-1 mutation associated with diabetes, E224K, disrupts the ability of PCIF1 to inhibit PDX-1 transactivation, suggesting that the interaction between PDX-1 and PCIF1 is required for normal glucose homeostasis. Inhibition of transactivation occurs by a mechanism distinct from the classical role of POZ domains to recruit co-repressors and histone deacetylases. Understanding the functional roles of PCIF1 domains may have application to therapeutic b-cell replacement strategies involving PDX-1 for the treatment of diabetes.

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Minireview: Transcriptional Regulation in Pancreatic Development

Cited by 359 publications

References 109 publications

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

Two conserved domains in PCIF1 mediate interaction with pancreatic transcription factor PDX‐1

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