Adar1 deletion causes degeneration of the exocrine pancreas via Mavs-dependent interferon signaling

• Published in: Development (Cambridge) Vol. 150; no. 2
• Main Authors: Rupani, Dhwani N, Thege, Fredrik I, Chandra, Vidhi, Rajaei, Hajar, Cowan, Robert W, Wörmann, Sonja M, Le Roux, Olivereen, Malaney, Prerna, Manning, Sara L, Hashem, Jack, Bailey-Lundberg, Jennifer, Rhim, Andrew D, McAllister, Florencia
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.01.2023
• Subjects: Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Animals; Interferons - genetics; Interferons - metabolism; Mice; Pancreas, Exocrine - metabolism; Phenotype; Research Report; Interferon; Pancreatic development; Mouse; Mavs; Pancreatic homeostasis; Adar1
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.201097

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.