Dataset Information

Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

ABSTRACT: Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6(Delta endo)) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on beta cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6(Delta panc)) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6(Delta panc) animals survived to adulthood. HNF6(Delta panc) pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6(Delta panc) pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology.

SUBMITTER: Zhang H

PROVIDER: S-EPMC2783291 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

Zhang Hongjie H Ables Elizabeth Tweedie ET Pope Christine F CF Washington M Kay MK Hipkens Susan S Means Anna L AL Path Gunter G Seufert Jochen J Costa Robert H RH Leiter Andrew B AB Magnuson Mark A MA Gannon Maureen M

Mechanisms of development 20090918 11-12

Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lin ...[more]

PMID: 19766716

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Project description: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 Oc1Δpanc (Oc1fl/fl;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 Oc1Δpanc 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.

Dataset Information

Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

Publications

Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

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