Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene <i>ngn3</i>

Jacquemin, Patrick; Durviaux, Serge; Jensen, Jan; Godfraind, Catherine; Gradwohl, Gérard; Guillemot, François; Madsen, Ole; Carmeliet, Peter; Dewerchin, Mieke; Collen, Désiré; Rousseau, Guy; Lemaigre, Frédéric P.

doi:10.1128/mcb.20.12.4445-4454.2000

Cited by 305 publications

(323 citation statements)

References 35 publications

Supporting

Mentioning

297

Contrasting

Unclassified

Order By: Relevance

“…This leads to diabetes mellitus in the mice that survive until adulthood. These diabetic mice fail to increase their basal insulin secretion in response to glucose administration [17]. The phenotype of the hnf6-/-mice is not fully penetrant (our unpublished observations) and 20 to 25% of the mice do not show glucose intolerance.…”

Section: Liver Chromatin Over the Promoter Is Decondensed Even In Absmentioning

confidence: 72%

“…hnf6 null mice were selected in our laboratory and treated according to the principles of laboratory animal care of the University animal welfare committee. These mice have a defective development of the endocrine pancreas and they are diabetic [17]. As the penetrance of this phenotype is variable, the severity of diabetes was determined by a glucose tolerance test.…”

Section: Electrophoretic Mobility Shift Assays (Emsa)mentioning

confidence: 99%

“…Therefore, we hypothesized that Hss 2 and perhaps also other liver-specific DNase I Hss might disappear in the absence of HNF-6. To investigate this possibility, we repeated the experiment with liver from mice in which we have inactivated the hnf6 gene by homologous recombination [17]. We found earlier that inactivation of the hnf6 gene leads to incomplete maturation of beta cells and to perturbed structure of the islets of Langerhans [17].…”

Section: Liver Chromatin Over the Promoter Is Decondensed Even In Absmentioning

confidence: 99%

“…Two members of this class are present in mammalian liver, namely HNF-6 and Onecut-2 (OC-2) [14]. HNF-6 is expressed in the embryonic liver and pancreas [15,16] and it plays an important role in the development of these organs [17]. In the adult, HNF-6 is involved in the liver-specific control of several genes of glucose metabolism, e.g.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

et al. 2002

View full text Add to dashboard Cite

Aims/hypothesis. Glucokinase plays a key role in glucose homeostasis and the expression of its gene is differentially regulated in pancreatic beta cells and in the liver through distinct promoters. The factors that determine the tissue-specific expression of the glucokinase gene are not known. Putative binding sites for hepatocyte nuclear factor (HNF)-6, the prototype of the ONECUT family of transcription factors, are present in the hepatic promoter of the glucokinase gene and in diabetic hnf6 knockout mice. We hypothesized that HNF-6 controls the activity of the hepatic glucokinase promoter. Methods. We tested the binding of recombinant HNF-6 to DNA sequences from the mouse hepatic glucokinase promoter in vitro and the effect of HNF-6 on promoter activity in transfected cells. We investigated in vivo the role of HNF-6 in mice by examining the effect of inactivating the hnf6 gene on glucokinase gene-specific deoxyribonuclease I hypersensitive sites in liver chromatin and on liver glucokinase mRNA concentration.Results. HNF-6 bound to the hepatic promoter of the glucokinase gene and stimulated its activity. Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value. Conclusions/interpretation. Although HNF-6 is not required to open chromatin of the hepatic promoter of the glucokinase gene, it stimulates transcription of the glucokinase gene in the liver. This could partly explain the diabetes observed in hnf6 knockout mice.

show abstract

Section: Liver Chromatin Over the Promoter Is Decondensed Even In Absmentioning

confidence: 72%

Section: Electrophoretic Mobility Shift Assays (Emsa)mentioning

confidence: 99%

Section: Liver Chromatin Over the Promoter Is Decondensed Even In Absmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Problems with forming the endocrine-competent progenitor pool within the maturing epithelial arbor fits with the finding of defects in HNF6 mutants as early as E15.5, and generation of a cystic multilayered ''piled up'' epithelium. The intercalated ducts, which we propose could normally become partitioned, relatively early on, from the main endocrine/duct-competent trunk epithelium as part of the program of architectural resolution of the epithelial plexus, can apparently still form and acini differentiate, but there are no second-wave endocrine cells (Jacquemin et al, 2000;Pierreux et al, 2006;Zhang et al, 2009). The dilated multilayered epithelial cells in the HNF6 null lack primary cilia but maintain polarity as marked by apical Mucin1 (Muc1).…”

Section: Exocrine Cell Development Ducts and Centroacinar Cellsmentioning

confidence: 85%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

594

View full text Add to dashboard Cite

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,

show abstract

Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

et al. 2018

View full text Add to dashboard Cite

Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar–ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix‐loop‐helix (bHLH) factors MIST1 and PTF1a coordinate an acinar‐specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re‐establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar‐specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer‐associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP‐binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease.

show abstract

Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene ngn3

Cited by 305 publications

References 35 publications

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

Pancreas organogenesis: From bud to plexus to gland

Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

Contact Info

Product

Resources

About