IPF1, a homeodomain-containing transactivator of the insulin gene.

Ohlsson, Helena; Karlsson, Kurt; Edlund, Thomas

doi:10.1002/j.1460-2075.1993.tb06109.x

Cited by 834 publications

(632 citation statements)

References 36 publications

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“…Moreover, nFOXO1 was highly co-localised with PDX-1 + and NGN3 + cell populations during this developmental period. These findings are consistent with observations in the mouse, where FOXO1 is widely produced between e9.5 and 14.5 [10][11][12][13][14], a stage corresponding to the human developmental window examined in the present study. However, following this period in the mouse, a global decline in the distribution of FOXO1 has been observed, whereby this transcription factor becomes restricted to endocrine progenitor cells by e17.5 and eventually becomes limited to beta cells postnatally [12,13].…”

Section: Discussionsupporting

confidence: 94%

“…During mouse pancreatic organogenesis, FOXO1 and PDX-1 share similar production patterns; both are widely produced in the pancreatic epithelium between embryonic day (e) 9.5 and 14.5 and become exclusively produced postnatally in beta cells [10][11][12][13][14]. More recently, FOXO1 has been reported in murine myoblasts to interact with Notch signalling to regulate hairy and enhancer of split 1 (Hes1) gene expression; HES1 is a well-known repressor of neurogenin 3 (Ngn3 [also known as Neurog3]) [15,16].…”

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: Discussionsupporting

confidence: 94%

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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“…The pancreatic islet restricted transcription factors BETA2/NeuroD and PDX1, which bind to the E1 and A3 elements, have been isolated. Mice deficient in these transcription factors revealed these factors to be indispensable for islet cell development and insulin gene expression [46][47][48][49]. In addition, mutations in the BETA2 and PDX1 genes were found in some patients with maturity-onset diabetes of the young (MODY) [50,51].…”

Section: Discussionmentioning

confidence: 99%

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Kajihara

Sone

Amemiya

et al. 2003

Biochemical and Biophysical Research Communications

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Large Maf transcription factors, which are members of the basic leucine zipper (b-Zip) superfamily, have been reported to be involved in embryonic development and cell differentiation. Previously, we isolated a novel zebrafish large Maf cDNA, somite Maf1 (SMaf1), which possesses transactivational activity within its N-terminus domain. To elucidate SMaf1 function in mammals, we tried to isolate the mouse homologue of zebrafish SMaf1. We isolated the mouse homologue of zebrafish SMaf1, which is the same molecule as the recently reported MafA. MafA mRNA was detected in formed somites, head neural tube, and liver cells in the embryos. In the adult mouse, MafA transcript was amplified in the brain, lung, spleen, and kidney by RT-PCR. MafA mRNA was also detectable in b-cell line. Next, we analyzed the transcriptional activity of MafA using rat insulin promoters I and II (RIPI and II), since a part of RIP sequence was similar to the Maf recognition element (MARE) and MafA was expressed in pancreatic b-cells. MafA was able to activate transcription from RIPII, but not RIPI, in a dose dependent manner and the activity was dependent on RIPE3b/C1 sequences. In addition, the amount of MafA protein was regulated by glucose concentration. These results indicate that MafA is the homologue of zebrafish SMaf1 and acts as a transcriptional activator of the insulin gene promoter through the RIPE3b element.

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“…It was the first gene shown to be cell-autonomously required for some of the earliest steps of pancreas formation, in mice and humans (Ohlsson et al, 1993;Jonsson et al, 1994;Offeld et al, 1996;Stoffers et al, 1997). Pdx1 is expressed in the dorsal and ventral pre-pancreatic endoderm at E8.5, and its expression is maintained at much later stages in the b-cells.…”

Section: Pdx1mentioning

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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IPF1, a homeodomain-containing transactivator of the insulin gene.

Cited by 834 publications

References 36 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

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Pancreas organogenesis: From bud to plexus to gland

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