Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3

Abstract

Background: Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylargininein mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However,its role in pancreas development has not yet been elucidated. Methods: Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for theirmetabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells. Results: Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass weresignificantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrinecell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expressionof NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradationof NGN3. Conclusion: PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.