Variaciones de la configuración ductal pancreática: factor predisponente de pancreatitis recurrente / Variations of pancreatic ductal configuration: predisposing factor of recurrent pancreatitis

El páncreas es un órgano de origen endodérmico, que se desarrolla de dos esbozos intestinales separados, uno dorsal y otro ventral,a partir de la cuarta o quinta semana de gestación. El páncreas se origina en el intestino anterior en la parte correspondiente a lafutura segunda porción duodenal. Allí se originan dos brotes: uno posterior o dorsal que aparece a principios de la cuarta semanay crece rápidamente en el mesenterio dorsal y el otro brote es anterior o ventral. Este último da origen a dos brotes, uno origina unaparte del páncreas y otro a la vía biliar e hígado. Existen diferentes variantes anatómicas, derivadas de este desarrollo embrionario;su conocimiento es de vital importancia en pacientes con persistencia de dolor abdominal y episodios de pancreatitis recurrente.El objetivo de este artículo es una revisión de las variantes anatómicas del conducto pancreático que pueden manifestarse como pancreatitis idiopática recurrente. (AU)

The pancreas is an organ of endodermal origin, which develops from two separate intestinal sketches, one dorsal and one ventral,from the fourth or fifth week of gestation. The pancreas originates in the anterior intestine in the part corresponding to the futuresecond duodenal portion. There two shoots originate: one posterior or dorsal that appears at the beginning of the fourth week andgrows rapidly in the dorsal mesentery and the other outbreak is anterior or ventral. The latter gives rise to two outbreaks, oneoriginates a part of the pancreas and another to the bile duct and liver. There are different anatomical variants, derived from thisembryonic development; their knowledge is of vital importance in patients with persistent abdominal pain and episodes of recurrentpancreatitis. The objective of this article is a review of the anatomical variants of the pancreatic duct that can manifest as recurrent idiopathic pancreatitis. (AU)

Pancreatic Ductal Deletion of Hnf1b Disrupts Exocrine Homeostasis, Leads to Pancreatitis, and Facilitates Tumorigenesis.

BACKGROUND & AIMS: The exocrine pancreas consists of acinar cells that produce digestive enzymes transported to the intestine through a branched ductal epithelium. Chronic pancreatitis is characterized by progressive inflammation, fibrosis, and loss of acinar tissue. These changes of the exocrine tissue are risk factors for pancreatic cancer. The cause of chronic pancreatitis cannot be identified in one quarter of patients. Here, we investigated how duct dysfunction could contribute to pancreatitis development. METHODS: The transcription factor Hnf1b, first expressed in pancreatic progenitors, is strictly restricted to ductal cells from late embryogenesis. We previously showed that Hnf1b is crucial for pancreas morphogenesis but its postnatal role still remains unelucidated. To investigate the role of pancreatic ducts in exocrine homeostasis, we inactivated the Hnf1b gene in vivo in mouse ductal cells. RESULTS: We uncovered that postnatal Hnf1b inactivation in pancreatic ducts leads to chronic pancreatitis in adults. Hnf1bΔduct mutants show dilatation of ducts, loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis. We deciphered the early events involved, with down-regulation of cystic disease-associated genes, loss of primary cilia, up-regulation of signaling pathways, especially the Yap pathway, which is involved in acinar-to-ductal metaplasia. Remarkably, Hnf1bΔduct mutants developed pancreatic intraepithelial neoplasia and promote pancreatic intraepithelial neoplasia progression in concert with KRAS. We further showed that adult Hnf1b inactivation in pancreatic ducts is associated with impaired regeneration after injury, with persistent metaplasia and initiation of neoplasia. CONCLUSIONS: Loss of Hnf1b in ductal cells leads to chronic pancreatitis and neoplasia. This study shows that Hnf1b deficiency may contribute to diseases of the exocrine pancreas and gains further insight into the etiology of pancreatitis and tumorigenesis.

p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate.

The mechanism of how organ shape emerges and specifies cell fate is not understood. Pancreatic duct and endocrine lineages arise in a spatially distinct domain from the acinar lineage. Whether these lineages are pre-determined or settle once these niches have been established remains unknown. Here, we reconcile these two apparently opposing models, demonstrating that pancreatic progenitors re-localize to establish the niche that will determine their ultimate fate. We identify a p120ctn-regulated mechanism for coordination of organ architecture and cellular fate mediated by differential E-cadherin based cell sorting. Reduced p120ctn expression is necessary and sufficient to re-localize a subset of progenitors to the peripheral tip domain, where they acquire an acinar fate. The same mechanism is used re-iteratively during endocrine specification, where it balances the choice between the alpha and beta cell fates. In conclusion, organ patterning is regulated by p120ctn-mediated cellular positioning, which precedes and determines pancreatic progenitor fate.

Connexin 30.2 is expressed in exocrine vascular endothelial and ductal epithelial cells throughout pancreatic postnatal development.

Previously we have demonstrated that the GJ protein connexin 30.2 (Cx30.2) is expressed in pancreatic beta cells and endothelial cells (ECs) of the islet. In the present study, we address whether Cx30.2 is expressed in the exocrine pancreas, including its vascular system. For this, adult mouse pancreatic sections were double labeled with specific antibodies against Cx30.2 and CD31, an endothelial cell marker, or with anti-α-actin smooth muscle, a smooth muscle cell (SMC) marker or anti-mucin-1, a marker of epithelial ductal cells, using immunofluorescence (IF) studies. Cx30.2-IF hot spots were found at junctional membranes of exocrine ECs and SMCs of blood vessels. Furthermore, Cx30.2 was localized in mucin-1 positive cells or epithelial ductal cells. Using immunohistochemistry (IHC) studies, it was found that in vessels and ducts of different diameters, Cx30.2 was also expressed in these cell types. In addition, it was found that Cx30.2 is already expressed in these cell types in pancreatic sections of 3, 14 and 21 days postpartum. Moreover, this cell specific pattern of expression was also found in the adult rat, hamster and guinea pig pancreas. Expression of Cx30.2 mRNA and protein in the pancreas of all these species was confirmed by RT-PCR and Western blot studies. Overall, our results suggest that intercellular coupling mediated by Cx30.2 intercellular channels may synchronize the functional activity of ECs and SMCs of vascular cells, as well as of epithelial ductal cells after birth.

Acinar cells in the neonatal pancreas grow by self-duplication and not by neogenesis from duct cells.

Pancreatic acinar cells secrete digestive enzymes necessary for nutrient digestion in the intestine. They are considered the initiating cell type of pancreatic cancer and are endowed with differentiation plasticity that has been harnessed to regenerate endocrine beta cells. However, there is still uncertainty about the mechanisms of acinar cell formation during the dynamic period of early postnatal development. To unravel cellular contributions in the exocrine acinar development we studied two reporter mouse strains to trace the fate of acinar and duct cells during the first 4 weeks of life. In the acinar reporter mice, the labelling index of acinar cells remained unchanged during the neonatal pancreas growth period, evidencing that acinar cells are formed by self-duplication. In line with this, duct cell tracing did not show significant increase in acinar cell labelling, excluding duct-to-acinar cell contribution during neonatal development. Immunohistochemical analysis confirms massive levels of acinar cell proliferation in this early period of life. Further, also increase in acinar cell size contributes to the growth of pancreatic mass.We conclude that the growth of acinar cells during physiological neonatal pancreas development is by self-duplication (and hypertrophy) rather than neogenesis from progenitor cells as was suggested before.

Endocrine pancreas engineered using porcine islets and partial pancreatic scaffolds.

OBJECTIVES: Because therapeutic options for severe diabetes are currently limited, there is a continuing need for new therapeutic strategies, especially in the field of regenerative medicine. Collaborative efforts across the fields of tissue engineering technology and islet biology may be able to create functionally engineered islets capable of restoring endocrine function in patients with insulin-dependent diabetes. METHODS: This engineered scaffold was seeded with isolated primary porcine islets via the pancreatic duct using a multi-step infusion technique. Endocrine function of perfusion-cultured islets in the native scaffold was analyzed by immunohistochemical staining of insulin and glucagon as well as by the insulin stimulation test. RESULTS: The pancreas in this large animal could be uniformly decellularized by perfusion with trypsin and TritonX-100 via the pancreatic duct, as shown by positive staining of extracellular matrix (ECM) components. These scaffolds derived from porcine pancreas were able to maintain the cellular integrity of islets that had repopulated the parenchymal space, which is fundamental for the restoration of endocrine function. Insulin release up to four days after islet infusion was maintained. CONCLUSIONS: This scaffold from a large animal maintained islet survival and function in the short-term, retaining the cells as a solid organ in the parenchymal space after infusion through the pancreatic duct. These results suggest that this scaffold is suitable for further fabrication of fully functional bioengineered endocrine pancreases when implanted in vivo. Therefore, it may represent a key improvement in the field of beta-cell replacement therapy. Nonetheless, the facilitation of longer-term islet survival and studies of implantation in vivo is required for successful clinical translation.

Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells.

A key question in diabetes research is whether new ß-cells can be derived from endogenous, nonendocrine cells. The potential for pancreatic ductal cells to convert into ß-cells is a highly debated issue. To date, it remains unclear what anatomical process would result in duct-derived cells coming to exist within preexisting islets. We used a whole-mount technique to directly visualize the pancreatic ductal network in young wild-type mice, young humans, and wild-type and transgenic mice after partial pancreatectomy. Pancreatic ductal networks, originating from the main ductal tree, were found to reside deep within islets in young mice and humans but not in mature mice or humans. These networks were also not present in normal adult mice after partial pancreatectomy, but TGF-ß receptor mutant mice demonstrated formation of these intraislet duct structures after partial pancreatectomy. Genetic and viral lineage tracings were used to determine whether endocrine cells were derived from pancreatic ducts. Lineage tracing confirmed that pancreatic ductal cells can typically convert into new ß-cells in normal young developing mice as well as in adult TGF-ß signaling mutant mice after partial pancreatectomy. Here the direct visual evidence of ducts growing into islets, along with lineage tracing, not only represents strong evidence for duct cells giving rise to ß-cells in the postnatal pancreas but also importantly implicates TGF-ß signaling in this process.

The ductal origin of structural and functional heterogeneity between pancreatic islets.

Islets form in the pancreas after the first endocrine cells have arisen as either single cells or small cell clusters in the epithelial cords. These cords constitute the developing pancreas in one of its earliest recognizable stages. Islet formation begins at the time the cords transform into a branching ductal system, continues while the ductal system expands, and finally stops before the exocrine tissue of ducts and acini reaches its final expansion. Thus, islets continuously arise from founder cells located in the branching and ramifying ducts. Islets arising from proximal duct cells locate between the exocrine lobules, develop strong autonomic and sensory innervations, and pass their blood to efferent veins (insulo-venous efferent system). Islets arising from cells of more distal ducts locate within the exocrine lobules, respond to nerve impulses ending at neighbouring blood vessels, and pass their blood to the surrounding acini (insulo-acinar portal system). Consequently, the section of the ductal system from which an islet arises determines to a large extent its future neighbouring tissue, architecture, properties, and functions. We note that islets interlobular in position are frequently found in rodents (rats and mice), whereas intralobularly-located, peripheral duct islets prevail in humans and cattle. Also, we expound on bovine foetal Laguesse islets as a prominent foetal type of type 1 interlobular neuro-insular complexes, similar to neuro-insular associations frequently found in rodents. Finally, we consider the probable physiological and pathophysiological implications of the different islet positions within and between species.

Hepatocyte growth factor signaling in intrapancreatic ductal cells drives pancreatic morphogenesis.

In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908) , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

The adult mammalian pancreas contains separate precursors of pancreatic and neural crest developmental origins.

The developmental origin of a pancreatic precursor cell could provide clues to properties that may be crucial to its molecular regulation and therapeutic potential. Previously, lineage tracing experiments showed that multipotent precursors in mouse islets had a pancreatic and not a neural crest developmental origin. However, a different Cre reporter system reveals that there is, in fact, a rare population of proliferative cells in the pancreas that is descended from the Wnt1 neural crest lineage, in addition to the majority population descended from the Pdx1 pancreatic lineage. These two proliferative cell populations are distinct in their gene expression and differentiation potential. This evidence suggests that there are at least two distinct types of precursors present in adult pancreatic islets, one of pancreatic origin and one of neural crest origin.

Pancreatic ductal cells in development, regeneration, and neoplasia.

The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

Transdifferentiation of tadpole pancreatic acinar cells to duct cells mediated by Notch and stromelysin-3.

The tadpole pancreas has differentiated acinar cells but an underdeveloped ductal system. At the climax of metamorphosis thyroid hormone (TH) induces the tadpole acinar cells to dedifferentiate to a progenitor state. After metamorphosis is complete the exocrine pancreas redifferentiates in the growing frog forming a typical vertebrate pancreas including a complex ductal system. A micro array analysis found that TH up regulates stromelysin 3 (ST3, matrix metalloproteinase 11) in the exocrine pancreas at metamorphic climax. Transgenic tadpoles were prepared with an elastase promoter driving either the ST3 gene or the constitutively active form of Notch (IC). Expression of the transgenes was controlled by the tetracycline system. A few days after either of these transgenes is activated by doxycycline the pancreatic acinar cells turn into duct-like cells. This transdetermination occurs without cell division since both acinar and ductal markers can be visualized transiently in the same cell. We propose that remodeling of the tadpole acinar cells is initiated when ST3 is up regulated by TH. Stromelysin-3 then cleaves and activates Notch.

Adaptation to intermittent stress promotes maintenance of beta-cell compensation: comparison with food restriction.

Intermittent restraint stress delays hyperglycemia in ZDF rats better than pair feeding. We hypothesized that intermittent stress would preserve beta-cell mass through distinct mechanisms from food restriction. We studied temporal effects of intermittent stress on beta-cell compensation during pre-, early, and late diabetes. Six-week-old obese male ZDF rats were restraint-stressed 1 h/day, 5 days/wk for 0, 3, 6, or 13 wk and compared with age-matched obese ZDF rats that had been food restricted for 13 wk, and 19-wk-old lean ZDF rats. Thirteen weeks of stress and food restriction lowered cumulative food intake 10-15%. Obese islets were fibrotic and disorganized and not improved by stress or food restriction. Obese pancreata had islet hyperplasia and showed evidence of neogenesis, but by 19 wk old beta-cell mass was not increased, and islets had fewer beta-cells that were hypertrophic. Both stress and food restriction partially preserved beta-cell mass at 19 wk old via islet hypertrophy, whereas stress additionally lowered alpha-cell mass. Concomitant with maintenance of insulin responses to glucose, stress delayed the sixfold decline in beta-cell proliferation and reduced beta-cell hypertrophy, translating into 30% more beta-cells per islet after 13 wk. In contrast, food restriction did not improve insulin responses or beta-cell hyperplasia, exacerbated beta-cell hypertrophy, and resulted in fewer beta-cells and greater alpha-cell mass than with stress. Thus, preservation of beta-cell mass with adaptation to intermittent stress is related to beta-cell hyperplasia, maintenance of insulin responses to glucose, and reductions in alpha-cell mass that do not occur with food restriction.

Remodeling the exocrine pancreas at metamorphosis in Xenopus laevis.

At metamorphosis the Xenopus laevis tadpole exocrine pancreas remodels in two stages. At the climax of metamorphosis thyroid hormone (TH) induces dedifferentiation of the entire exocrine pancreas to a progenitor state. The organ shrinks to 20% of its size, and approximately 40% of its cells die. The acinar cells lose their zymogen granules and approximately 75% of their RNA. The mRNAs that encode exocrine-specific proteins (including the transcription factor Ptf1a) undergo almost complete extinction at climax, whereas PDX-1, Notch-1, and Hes-1, genes implicated in differentiation of the progenitor cells, are activated. At the end of spontaneous metamorphosis when the endogenous TH has reached a low level, the pancreas begins to redifferentiate. Exogenous TH induces the dedifferentiation phase but not the redifferentation phase. The tadpole pancreas lacks the mature ductal system that is found in adult vertebrate pancreases, including the frog. Exocrine pancreases of transgenic tadpoles expressing a dominant negative form of the TH receptor controlled by the elastase promoter are resistant to TH. They do not shrink when subjected to TH. Their acinar cells do not dedifferentiate at climax, nor do they down-regulate exocrine-specific genes or activate Notch-1 and Hes-1. Even 2 months after metamorphosis these frogs have not developed a mature ductal system and the acinar cells are abnormally arranged. The TH-dependent dedifferentiation of the tadpole acinar cells at climax is a necessary step in the formation of a mature frog pancreas.

Transforming growth factor beta is a critical regulator of adult human islet plasticity.

Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFbeta signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFbeta in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFbeta caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFbeta, antibody-mediated neutralization of this endogenously released TGFbeta improved DLS formation rates, suggesting local TGFbeta concentrations may in fact be higher. Time course studies indicated that TGFbeta signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFbeta signaling molecules suggested that the action of TGFbeta is directly on the beta-cell to inhibit apoptosis and thus stabilize endocrine phenotype.

Role of FGF1, FGF2 and FGF7 in the development of the pancreas from control and streptozotocin-treated hamsters.

Although progress has been made with respect to the growth and transcription factors implicated in pancreatic development, many questions remain unsolved. It has been established that during embryonic life, both endocrine and acinar cells are derived from pancreatic epithelial precursor cells. Growth factors control the proliferation of precursor cells and their ability to differentiate into mature cells, both in pre-natal and in early post-natal life. Pancreatic development during the early post-natal period is an area of great interest for many scientists. In this study we have examined the structure characteristics, functional and proliferative activity of control and diabetic hamster pancreatic ductal, exocrine and beta cells, following treatment with FGFs 1, 2 and 7 in vitro. Light and electron microscopic studies indicated active synthetic processes in these cells under the influence of the investigated FGFs. In our experimental model of diabetes, the labelling index of the cells was significantly higher than in corresponding control groups of hamsters. We established that FGF2 at a concentration of 10 ng/l was responsible for the most prominent effect on ductal cells and beta cells in the diabetic groups. FGF1 at a concentration of 10 ng/l displayed the highest stimulatory effect on exocrine cells in the diabetic groups at post-natal day 10. Taken together these data strongly suggest that FGF1 and FGF2 induce proliferation of pancreatic epithelial cells during the early post-natal period whereas FGF7 is not strictly specific for pancreatic cell proliferation.

Induced cell clustering enhances islet beta cell formation from human cultures enriched for pancreatic ductal epithelial cells.

A better understanding of the culture conditions that stimulate in vitro beta-cell differentiation from islet precursors would be useful for optimizing the production of tissue-engineered islets. In this study, high- and low-adherent substrates and high- and low-serum media were used to control the clustering of human pancreatic ductal epithelial cells and to determine its effect on their transdifferentiation to beta cells. While the initial epithelial cell cultures were devoid of any beta cells as assessed by dithizone staining, dithizone+ cells were generated during the next 3 weeks under all culture conditions. Although the rate of transdifferentiation was low, a approximately 4-fold greater number and percentage of dithizone+ cells were generated following 23-24 days of culture in the least adherent conditions (low-serum medium, low-adherent substrate), which stimulated cell clustering to the highest degree. Insulin immunohistochemistry data correlated well with the dithizone data (r(2) = 0.99), evidence that dithizone is a reliable measure of insulin+ cells. The preferential distribution of the dithizone+ cells to regions of cell aggregation and the increased efficiency of transdifferentiation in conditions that promote cell clustering suggest that cell-cell interactions and/or cell shape changes are important to the transdifferentiation of adult pancreatic ductal epithelial cells to beta cells in vitro.

BMP4 regulates pancreatic progenitor cell expansion through Id2.

Inhibitor of DNA binding (Id) proteins bind to and inhibit the function of basic helix-loop-helix (bHLH) transcription factors including those that regulate pancreatic development. Moreover, bone morphogenetic proteins (BMPs) regulate the expression of Ids. We hypothesized that BMP4 and Id proteins play a role in the expansion and differentiation of epithelial progenitor cells. We demonstrate that BMP4 induces the expression of Id2 along with the expansion of AR42J pancreatic epithelial cells. Furthermore, neutralization of BMP4 significantly reduced duct epithelial cell expansion in a mouse model of islet regeneration. BMP4 stimulation promotes Id2 binding to the bHLH transcription factor NeuroD, which is required for the differentiation of pancreatic islet cells. Therefore, our results indicate that BMP4 stimulation blocks the differentiation of endocrine progenitor cells and instead promotes their expansion thereby revealing a novel paradigm of signaling explaining the balance between expansion and differentiation of pancreatic duct epithelial progenitors. Understanding the mechanisms of BMP and Id function elucidates a key step during pancreas embryogenesis, which is important knowledge for expanding pancreatic progenitors in vitro.

The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse.

BACKGROUND & AIMS: A number of hereditary polycystic diseases are associated with formation of cysts within the pancreatic ducts. The cysts result from abnormal tubulogenesis, but how normal pancreatic duct development is controlled remains poorly understood. Here, we investigate the transcriptional mechanisms that control pancreatic duct development by addressing the role of the transcription factor hepatocyte nuclear factor (HNF)-6. METHODS: Using immunostaining, we have determined the expression pattern of HNF-6 in pancreatic ducts during mouse development. Hnf6 null mice at various stages of development were studied by immunolocalization methods to assess the morphology, differentiation, and proliferation status of ductal cells. The expression of genes involved in hereditary polycystic diseases was determined by real-time, reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: We show that HNF-6 is expressed in the pancreatic duct epithelium throughout development and that, in the absence of HNF-6, duct morphogenesis is perturbed. Although development of the intercalated ducts is normal, cysts appear within the interlobular and intralobular ducts. This is associated with abnormal development of primary cilia at the apical pole of the duct cells and with reduced expression of a set of genes involved in polycystic diseases, namely those coding for HNF-1beta and for the cilium-associated proteins polyductin/fibrocystin and cystin. CONCLUSIONS: We identify HNF-6 as the first transcriptional regulator of pancreatic duct development and reveal the existence of different regulatory mechanisms in distinct duct compartments. HNF-6 controls a network of genes involved in cilium formation and in hereditary polycystic diseases. Finally, HNF-6 deficiency represents a genetically defined model of pancreatic cystic disease.