Notch signalling controls pancreatic cell differentiation

Apelqvist, Åsa; Li, Hao; Sommer, Lukas; Beatus, Paul; Anderson, David J.; Honjo, Tasuku; Angelis, Martin Hrabé de; Lendahl, Urban; Edlund, Helena

doi:10.1038/23716

Cited by 1,069 publications

(1,118 citation statements)

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“…Disruption of Notch signalling or its downstream mediators, including HES1, causes widespread expression of Ngn3 in the murine pancreas and accelerated endocrine differentiation [38,39]. Following FOXO1 silencing, a significant decrease in HES1 gene expression and protein abundance was observed in the human fetal islets.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2009

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“…These include Notch1-4, Deltalike 1 (Dll1), Dll3, Jagged1, Jagged2, Serrate1, and Serrate2 (Lammert et al, 2000;Jensen et al, 2000b). Mice deficient for various Notch pathway components, such as RBPJ, Dll1, and Hes1, display pancreatic hypoplasia resulting from precocious endocrine differentiation that causes progenitor pool depletion (Apelqvist et al, 1999;Jensen et al, 2000b;Fujikura et al, 2006). Furthermore, overexpressing Notch3 ICD , which represses Notch1-mediated upregulation of Hes1 in vivo, also results in reduced pancreas size and epithelial branching, with concurrent accelerated endocrine differentiation (Apelqvist et al, 1999).…”

Section: Notch Signaling In Early Pancreatic Progenitor Developmentmentioning

confidence: 99%

“…Mice deficient for various Notch pathway components, such as RBPJ, Dll1, and Hes1, display pancreatic hypoplasia resulting from precocious endocrine differentiation that causes progenitor pool depletion (Apelqvist et al, 1999;Jensen et al, 2000b;Fujikura et al, 2006). Furthermore, overexpressing Notch3 ICD , which represses Notch1-mediated upregulation of Hes1 in vivo, also results in reduced pancreas size and epithelial branching, with concurrent accelerated endocrine differentiation (Apelqvist et al, 1999). Conversely, mice expressing a constitutively active Notch1 Intracellular Domain (N1ICD) over the Pdx1 þ endoderm have greatly impaired endocrine and exocrine differentiation, and the hypoplastic pancreatic epithelium is effectively trapped in the undifferentiated state appropriate to when the NICD expression is activated (Hald et al, 2003;Murtaugh et al, 2003).…”

Section: Notch Signaling In Early Pancreatic Progenitor Developmentmentioning

confidence: 99%

“…Mice lacking Ngn3 function fail to develop endocrine cells , whereas ectopic Ngn3 expression under the Pdx1 promoter induces premature differentiation of the entire pancreatic bud progenitor pool into endocrine cells with predominantly acells (Apelqvist et al, 1999;Schwitzgebel et al, 2000). Lineage tracing studies showed that all endocrine cell types seem to be born from Ngn3-expressing endocrine progenitors (Gu et al, 2002).…”

Section: Endocrine Specificationmentioning

confidence: 99%

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Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

589

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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 b-cells. Developmental Dynamics 240:530-565,

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“…The phenotypic conversion from biliary to pancreatic development in the Hes1 mutant mice prompted us to examine the expression of Hes1 and Neurog3 (encoding neurogenin 3) in the developing biliary system to see whether the pancreatic differentiation program [5][6][7][8] operates ectopically in the mutant. In situ hybridization showed that Hes1 was expressed in the epithelial cells of the extrahepatic biliary system throughout normal cholangiogenesis (Fig.…”

mentioning

confidence: 99%