Unknown,Transcriptomics,Genomics,Proteomics

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Effect of fbw7 deletion in mouse pancreatic ducts

ABSTRACT: The adult pancreas is capable of limited regeneration after injury, but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into β-cells. The induced β-cells resemble islet β-cells in morphology and histology, express genes essential for β-cell function, and release insulin upon glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type. We used microarray to compare adult mouse fbw7 knock out ductal cells with bonafide beta cells In order to isolate fbw7 ko, fbw7 wt ductal cells and beta cells we used adult mice with the following genotypes: MIP-GFP (beta cells are constitutively labelled with GFP), Ck19-CreERT; R26-LSL-YFP; Fbw7 +/+ (ductal cells are labelled with YFP upon tamoxifen injection) and Ck19-CreERT; R26-LSL-YFP; Fbw7 F/F mice (ductal cells are labelled with YFP upon tamoxifen injection). 30000 GFP+ cells were isolated by FACS-sorting. RNA was extracted and amplified using NuGEN kit.

ORGANISM(S): Mus musculus

SUBMITTER: Rocio Sancho

PROVIDER: E-GEOD-58969 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion often result in chronic pancreatitis. Although the physiological mechanism of ductal secretion is known, its transcriptional control is not well characterized. Here, we investigate the role of the transcription factor Hematopoietically-expressed homeobox protein (Hhex) in pancreatic secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histological and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells (PDCs) were isolated to discover differentially expressed transcripts upon acute Hhex ablation. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia did not result from perturbations in primary cilia, but was consistent with the effects of primary ductal hypertension. RNA-seq analysis of Hhex-ablated PDCs indicated the G-protein coupled receptor Natriuretic peptide receptor 3, implicated in paracrine signaling, was upregulated 4.70-fold. Conclusions: Although Hhex is dispensable for adult pancreatic function, ablation of Hhex in pancreatic progenitors results in profound pancreatitis that is consistent with primary ductal hypertension. Our data highlight the critical role of paracrine signaling in maintaining ductal homeostasis, especially in early life, and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. Pancreatic primary ductal cells (PDCs) were isolated from uninduced adult HhexL/L;Sox9CreERT2 (n=2) and littermate control HhexL/L (n=2) mice. PDCs were treated with 500nM 4-hydroxytamoxifen in vitro for 4 days, and then RNA was collected for transcriptome analysis.

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Effect of fbw7 deletion in mouse pancreatic ducts

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