CFTR represses a PDX1 axis to govern pancreatic ductal cell fate
Summary: Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422402618X |
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| author | Pavana G. Rotti Yaling Yi Grace Gasser Feng Yuan Xingshen Sun Idil Apak-Evans Peipei Wu Guangming Liu Soon Choi Rosie Reeves Attilina E. Scioneaux Yulong Zhang Michael Winter Bo Liang Nathan Cunicelli Aliye Uc Andrew W. Norris Lori Sussel Kristen L. Wells John F. Engelhardt |
| author_facet | Pavana G. Rotti Yaling Yi Grace Gasser Feng Yuan Xingshen Sun Idil Apak-Evans Peipei Wu Guangming Liu Soon Choi Rosie Reeves Attilina E. Scioneaux Yulong Zhang Michael Winter Bo Liang Nathan Cunicelli Aliye Uc Andrew W. Norris Lori Sussel Kristen L. Wells John F. Engelhardt |
| author_sort | Pavana G. Rotti |
| collection | DOAJ |
| description | Summary: Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. The phenotypic changes in CF ductal epithelium and their impact on islet function are unknown. Using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3β activation. In the absence of CFTR protein, centroacinar cells adopted a bipotent progenitor-like state associated with enhanced WNT/β-Catenin, transforming growth factor β (TGF-β), and AKT signaling. We show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF. |
| format | Article |
| id | doaj-art-adf31ce97f1349c6913af02b6606f692 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-adf31ce97f1349c6913af02b6606f6922024-12-22T05:29:13ZengElsevieriScience2589-00422024-12-012712111393CFTR represses a PDX1 axis to govern pancreatic ductal cell fatePavana G. Rotti0Yaling Yi1Grace Gasser2Feng Yuan3Xingshen Sun4Idil Apak-Evans5Peipei Wu6Guangming Liu7Soon Choi8Rosie Reeves9Attilina E. Scioneaux10Yulong Zhang11Michael Winter12Bo Liang13Nathan Cunicelli14Aliye Uc15Andrew W. Norris16Lori Sussel17Kristen L. Wells18John F. Engelhardt19Whitehead Institute, MIT, Cambridge, MA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USADepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USAStead Family Department of Pediatrics, Carver College of Medicine, Iowa City, IA, USACenter for Gene Therapy, Carver College of Medicine, University of Iowa, Iowa City, IA, USABarbara Davis Center for Childhood Diabetes, University of Colorado Anschutz, Medical Campus, Aurora, CO, USABarbara Davis Center for Childhood Diabetes, University of Colorado Anschutz, Medical Campus, Aurora, CO, USA; Corresponding authorDepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Corresponding authorSummary: Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. The phenotypic changes in CF ductal epithelium and their impact on islet function are unknown. Using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3β activation. In the absence of CFTR protein, centroacinar cells adopted a bipotent progenitor-like state associated with enhanced WNT/β-Catenin, transforming growth factor β (TGF-β), and AKT signaling. We show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.http://www.sciencedirect.com/science/article/pii/S258900422402618XPhysiologyMolecular biologyCell biologyTranscriptomics |
| spellingShingle | Pavana G. Rotti Yaling Yi Grace Gasser Feng Yuan Xingshen Sun Idil Apak-Evans Peipei Wu Guangming Liu Soon Choi Rosie Reeves Attilina E. Scioneaux Yulong Zhang Michael Winter Bo Liang Nathan Cunicelli Aliye Uc Andrew W. Norris Lori Sussel Kristen L. Wells John F. Engelhardt CFTR represses a PDX1 axis to govern pancreatic ductal cell fate iScience Physiology Molecular biology Cell biology Transcriptomics |
| title | CFTR represses a PDX1 axis to govern pancreatic ductal cell fate |
| title_full | CFTR represses a PDX1 axis to govern pancreatic ductal cell fate |
| title_fullStr | CFTR represses a PDX1 axis to govern pancreatic ductal cell fate |
| title_full_unstemmed | CFTR represses a PDX1 axis to govern pancreatic ductal cell fate |
| title_short | CFTR represses a PDX1 axis to govern pancreatic ductal cell fate |
| title_sort | cftr represses a pdx1 axis to govern pancreatic ductal cell fate |
| topic | Physiology Molecular biology Cell biology Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S258900422402618X |
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