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Regulation of the Pancreatic Exocrine Differentiation Program and Morphogenesis by Onecut 1/Hnf6.
Kropp PA, Zhu X, Gannon M
(2019) Cell Mol Gastroenterol Hepatol 7: 841-856
MeSH Terms: Acinar Cells, Animals, Animals, Newborn, Base Sequence, Cell Differentiation, Cell Proliferation, Embryo, Mammalian, Epithelium, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factor 6, Mice, Morphogenesis, Pancreas, Exocrine
Show Abstract · Added March 29, 2019
BACKGROUND & AIMS - The Onecut 1 transcription factor (Oc1, a.k.a. HNF6) promotes differentiation of endocrine and duct cells of the pancreas; however, it has no known role in acinar cell differentiation. We sought to better understand the role of Oc1 in exocrine pancreas development and to identify its direct transcriptional targets.
METHODS - Pancreata from Oc1 (Oc1;Pdx1-Cre) mouse embryos and neonates were analyzed morphologically. High-throughput RNA-sequencing was performed on control and Oc1-deficient pancreas; chromatin immunoprecipitation sequencing was performed on wild-type embryonic mouse pancreata to identify direct Oc1 transcriptional targets. Immunofluorescence labeling was used to confirm the RNA-sequencing /chromatin immunoprecipitation sequencing results and to further investigate the effects of Oc1 loss on acinar cells.
RESULTS - Loss of Oc1 from the developing pancreatic epithelium resulted in disrupted duct and acinar cell development. RNA-sequencing revealed decreased expression of acinar cell regulatory factors (Nr5a2, Ptf1a, Gata4, Mist1) and functional genes (Amylase, Cpa1, Prss1, Spink1) at embryonic day (e) 18.5 in Oc1 samples. Approximately 1000 of the altered genes were also identified as direct Oc1 targets by chromatin immunoprecipitation sequencing, including most of the previously noted genes. By immunolabeling, we confirmed that Amylase, Mist1, and GATA4 protein levels are significantly decreased by P2, and Spink1 protein levels were significantly reduced and mislocalized. The pancreatic duct regulatory factors Hnf1β and FoxA2 were also identified as direct Oc1 targets.
CONCLUSIONS - These findings confirm that Oc1 is an important regulator of both duct and acinar cell development in the embryonic pancreas. Novel transcriptional targets of Oc1 have now been identified and provide clarity into the mechanisms of Oc1 transcriptional regulation in the developing exocrine pancreas. Oc1 can now be included in the gene-regulatory network of acinar cell regulatory genes. Oc1 regulates other acinar cell regulatory factors and acinar cell functional genes directly, and it can also regulate some acinar cell regulatory factors (eg, Mist1) indirectly. Oc1 therefore plays an important role in acinar cell development.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function.
Henley KD, Stanescu DE, Kropp PA, Wright CVE, Won KJ, Stoffers DA, Gannon M
(2016) Cell Rep 15: 2637-2650
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Count, Cell Differentiation, Embryo, Mammalian, Gene Dosage, Gene Expression Regulation, Developmental, Gene Ontology, Gene Regulatory Networks, Glucose, Hepatocyte Nuclear Factor 6, Heterozygote, Homeodomain Proteins, Homeostasis, Insulin-Secreting Cells, Mice, Multigene Family, Nerve Tissue Proteins, Stem Cells, Trans-Activators, Weaning
Show Abstract · Added July 5, 2016
Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (E)13.5, but defects in specification and differentiation were apparent at E15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.
Published by Elsevier Inc.
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21 MeSH Terms
Loss of HNF6 expression correlates with human pancreatic cancer progression.
Pekala KR, Ma X, Kropp PA, Petersen CP, Hudgens CW, Chung CH, Shi C, Merchant NB, Maitra A, Means AL, Gannon MA
(2014) Lab Invest 94: 517-27
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Disease Progression, Hepatocyte Nuclear Factor 6, Homeostasis, Humans, Liver Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Pancreatic Neoplasms
Show Abstract · Added March 26, 2014
Normal pancreatic epithelium progresses through various stages of pancreatic intraepithelial neoplasms (PanINs) in the development of pancreatic ductal adenocarcinoma (PDAC). Transcriptional regulation of this progression is poorly understood. In mouse, the hepatic nuclear factor 6 (Hnf6) transcription factor is expressed in ductal cells and at lower levels in acinar cells of the adult pancreas, but not in mature endocrine cells. Hnf6 is critical for terminal differentiation of the ductal epithelium during embryonic development and for pancreatic endocrine cell specification. We previously showed that, in mice, loss of Hnf6 from the pancreatic epithelium during organogenesis results in increased duct proliferation and altered duct architecture, increased periductal fibrosis and acinar-to-ductal metaplasia. Here we show that decreased expression of HNF6 is strongly correlated with increased severity of PanIN lesions in samples of human pancreata and is absent from >90% of PDAC. Mouse models in which cancer progression can be analyzed from the earliest stages that are seldom accessible in humans support a role for Hnf6 loss in progression from early- to late-stage PanIN and PDAC. In addition, gene expression analyses of human pancreatic cancer reveal decreased expression of HNF6 and its direct and indirect target genes compared with normal tissue and upregulation of genes that act in opposition to HNF6 and its targets. The negative correlation between HNF6 expression and pancreatic cancer progression suggests that HNF6 maintains pancreatic epithelial homeostasis in humans, and that its loss contributes to the progression from PanIN to ductal adenocarcinoma. Insight on the role of HNF6 in pancreatic cancer development could lead to its use as a biomarker for early detection and prognosis.
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11 MeSH Terms
Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.
Walter TJ, Vanderpool C, Cast AE, Huppert SS
(2014) Am J Pathol 184: 1479-88
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Epithelial Cells, Hepatocyte Nuclear Factor 6, Hepatocytes, Imaging, Three-Dimensional, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunohistochemistry, Keratin-19, Mice, Knockout, Plant Lectins, Portal Vein, Receptors, Notch, Regeneration, SOX9 Transcription Factor
Show Abstract · Added May 27, 2014
The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Onecut1 is essential for horizontal cell genesis and retinal integrity.
Wu F, Li R, Umino Y, Kaczynski TJ, Sapkota D, Li S, Xiang M, Fliesler SJ, Sherry DM, Gannon M, Solessio E, Mu X
(2013) J Neurosci 33: 13053-65, 13065a
MeSH Terms: Animals, Cell Count, Cell Differentiation, Cell Survival, Embryo, Mammalian, Eye Proteins, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neural Pathways, Neurogenesis, Neuroglia, Neurons, Protein Kinase C-alpha, Retina, Retinal Horizontal Cells, Synapses, Transcription Factors
Show Abstract · Added November 25, 2014
Horizontal cells are interneurons that synapse with photoreceptors in the outer retina. Their genesis during development is subject to regulation by transcription factors in a hierarchical manner. Previously, we showed that Onecut 1 (Oc1), an atypical homeodomain transcription factor, is expressed in developing horizontal cells (HCs) and retinal ganglion cells (RGCs) in the mouse retina. Herein, by knocking out Oc1 specifically in the developing retina, we show that the majority (∼80%) of HCs fail to form during early retinal development, implying that Oc1 is essential for HC genesis. However, no other retinal cell types, including RGCs, were affected in the Oc1 knock-out. Analysis of the genetic relationship between Oc1 and other transcription factor genes required for HC development revealed that Oc1 functions downstream of FoxN4, in parallel with Ptf1a, but upstream of Lim1 and Prox1. By in utero electroporation, we found that Oc1 and Ptf1a together are not only essential, but also sufficient for determination of HC fate. In addition, the synaptic connections in the outer plexiform layer are defective in Oc1-null mice, and photoreceptors undergo age-dependent degeneration, indicating that HCs are not only an integral part of the retinal circuitry, but also are essential for the survival of photoreceptors. In sum, these results demonstrate that Oc1 is a critical determinant of HC fate, and reveal that HCs are essential for photoreceptor viability, retinal integrity, and normal visual function.
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23 MeSH Terms
Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia.
Prévot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, Sempoux C, Xu X, Roelants V, Hald J, Bertrand L, Heimberg H, Konieczny SF, Dor Y, Lemaigre FP, Jacquemin P
(2012) Gut 61: 1723-32
MeSH Terms: Acinar Cells, Animals, Biomarkers, Tumor, Blotting, Western, Cell Transformation, Neoplastic, Cells, Cultured, Guinea Pigs, Hepatocyte Nuclear Factor 6, Humans, Metaplasia, Mice, Models, Animal, Pancreas, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, SOX9 Transcription Factor
Show Abstract · Added September 26, 2012
OBJECTIVE - Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated.
DESIGN - Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments.
RESULTS - Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells.
CONCLUSIONS - HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.
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16 MeSH Terms
Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program.
Stam FJ, Hendricks TJ, Zhang J, Geiman EJ, Francius C, Labosky PA, Clotman F, Goulding M
(2012) Development 139: 179-90
MeSH Terms: Animals, Bromodeoxyuridine, Cell Differentiation, Crosses, Genetic, Electrophysiology, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Immunohistochemistry, Interneurons, Mice, Spinal Cord, Time Factors, Transcription Factors
Show Abstract · Added February 17, 2012
The spinal cord contains a diverse array of physiologically distinct interneuron cell types that subserve specialized roles in somatosensory perception and motor control. The mechanisms that generate these specialized interneuronal cell types from multipotential spinal progenitors are not known. In this study, we describe a temporally regulated transcriptional program that controls the differentiation of Renshaw cells (RCs), an anatomically and functionally discrete spinal interneuron subtype. We show that the selective activation of the Onecut transcription factors Oc1 and Oc2 during the first wave of V1 interneuron neurogenesis is a key step in the RC differentiation program. The development of RCs is additionally dependent on the forkhead transcription factor Foxd3, which is more broadly expressed in postmitotic V1 interneurons. Our demonstration that RCs are born, and activate Oc1 and Oc2 expression, in a narrow temporal window leads us to posit that neuronal diversity in the developing spinal cord is established by the composite actions of early spatial and temporal determinants.
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15 MeSH Terms
Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo.
Vanderpool C, Sparks EE, Huppert KA, Gannon M, Means AL, Huppert SS
(2012) Hepatology 55: 233-43
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Cell Lineage, Cholestasis, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 6, Hepatocytes, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunoglobulin kappa-Chains, Integrases, Mice, Mice, Inbred Strains, Mice, Knockout, Receptors, Notch, SOX9 Transcription Factor, Signal Transduction
Show Abstract · Added December 5, 2013
UNLABELLED - Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y-related HMG box transcription factor 9).
CONCLUSION - HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes.
Copyright © 2011 American Association for the Study of Liver Diseases.
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17 MeSH Terms
A new set of classifications for ductal plate malformations.
Huppert SS
(2011) Hepatology 53: 1795-7
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Biomarkers, Congenital Abnormalities, Disease Models, Animal, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 4, Hepatocyte Nuclear Factor 6, Humans, Liver Diseases, Membrane Proteins, Mice, Mice, Knockout, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, SOX9 Transcription Factor
Added July 16, 2011
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17 MeSH Terms