Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation.

Jensen, Jan; Heller, R. Scott; Funder-Nielsen, T; Pedersen, Elisa; Lindsell, Claire E.; Weinmaster, Gerry; Madsen, Ole; Serup, Palle

doi:10.2337/diabetes.49.2.163

Cited by 400 publications

(356 citation statements)

References 27 publications

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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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“…During this period, ''second-wave'' endocrine cells emerge from within the trunk epithelium, their nascent formation being marked by transient high levels of the pro-endocrine TF Neurogenin3 (Ngn3) Schwitzgebel et al, 2000;Jensen et al, 2000a;Gu et al, 2002). Following specification, Ngn3 þ endocrine progenitors quickly differentiate into endocrine precursors, which delaminate from the epithelium and coalesce to form islets.…”

Section: The Secondary Transition: Onset Of Islet Duct and Acinar DImentioning

confidence: 99%

“…They further suggest that Ngn3 HI cells might have already been pre-committed or pre-biased to a specific endocrine cell lineage, but the timing of this selection-point needs much better analysis. A minor proportion of post-Ngn3 islet precursors divide, though only a few times, well into adulthood under physiological conditions (Jensen et al, 2000a;Degraz and Herrera, 2009). The remaining issue is how cells choose (or are instructed to choose) the proper/appropriate final hormone cell type; when is the choice taken with respect to the increase to transient Ngn3 HI production, before or after, how is it controlled, and can we override these choices either in vivo or in vitro towards a therapeutic advantage?…”

Section: Endocrine Specificationmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

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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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“…Although HNF-1α is involved in insulin secretion [15,16,17,18,19], it might have an additional role during the development of the pancreas. Thirdly, a cascade of transcription factors controls the development of pancreatic beta cells [14,20,21]. Earlier studies have shown neurogenin-3 and Nkx2.2 are expressed in endocrine cells in the early stage, while Isl1 and Pax6 are expressed by relatively mature endocrine cells [20,21,22,23,24,25,26].…”

mentioning

confidence: 99%

“…Thirdly, a cascade of transcription factors controls the development of pancreatic beta cells [14,20,21]. Earlier studies have shown neurogenin-3 and Nkx2.2 are expressed in endocrine cells in the early stage, while Isl1 and Pax6 are expressed by relatively mature endocrine cells [20,21,22,23,24,25,26]. If HNF-1α is expressed in the developing pancreas, what is its position in the developmental transcription cascade?…”

mentioning

confidence: 99%

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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Aims/hypothesis. One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1α. The pattern of HNF-1α expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1α protein expression in the developing mouse pancreas. Methods. Double immunofluorescence staining was carried out for HNF-1α and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1α mutant mice. Results. HNF-1α was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1α was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1α was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1α on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1α. However, HNF-1α immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1α. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1α (-/-) mice, but expression was markedly decreased in the diabetic stage. Conclusion/interpretation. HNF-1α is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1α might play a role during development. [Diabetologia (2002[Diabetologia ( ) 45:1142[Diabetologia ( -1153

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Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation.

Cited by 400 publications

References 27 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

Pancreas organogenesis: From bud to plexus to gland

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

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