Introduction Pancreatic duodenum homeobox 1 (Pdx1) expression is crucial for pancreatic organogenesis and is a key regulator of insulin gene expression. Hairy and enhancer of split 1 (Hes1) controls tissue morphogenesis by maintaining undifferentiated cells. Hes1 encodes a basic helix loop helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH genes, such as the endocrine determination gene neurogenin-3. Here, we generated a new pig model for diabetes by genetic engineering Pdx1 and Hes1 genes.
Research design and methods A transgenic (Tg) chimera pig with germ cells carrying a construct expressing Hes1 under the control of the Pdx1 promoter was used to mate with wild-type gilts to obtain Tg piglets.
Results The Tg pigs showed perinatal death; however, this phenotype could be rescued by insulin treatment. The duodenal and splenic lobes of the Tg pigs were slender and did not fully develop, whereas the connective lobe was absent. β cells were not detected, even in the adult pancreas, although other endocrine cells were detected, and exocrine cells functioned normally. The pigs showed no irregularities in any organs, except diabetes-associated pathological alterations, such as retinopathy and renal damage.
Conclusion Pdx1-Hes1 Tg pigs were an attractive model for the analysis of pancreatic development and testing of novel treatment strategies for diabetes.
- diabetes mellitus
- genetically modified
- animal experimentation
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MN and KH contributed equally.
Contributors MN and HirosN conception and design, financial support, collection and assembly of data, data analysis and interpretation, manuscript writing and final approval of manuscript. KH, MW, KN, KaO, TY, AU, HM and KU collection and assembly of data, data analysis and interpretation. HY and TN collection and assembly of data, data analysis and interpretation. KeO, EK and HiromN data analysis and interpretation.
Funding This research work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17K10527 and 20K08944 to MN), the Japan Agency for Medical Research and Development (Leading Advanced Projects for Medical Innovation, Generation of Functional Organs using Developmental Niche (to HirosN), Japan Science and Technology Agency (Exploratory Research for Advanced Technology, NAKAUCHI Stem Cell and Organ Regeneration (to HirosN), and the Meiji University International Institute for Bio-Resource Research (to MN and HirosN).
Disclaimer The funding organizations had no roles in the study’s design, data collection and analysis, the decision to publish, or the manuscript’s preparation.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All animal experiments in this study were approved by Meiji University’s Institutional Animal Care and Use Committee (IACUC07-0005, 14–0008, 19–0003).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.
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