Acinar cells are lost in both PKO and exPKO mice. The PERK-deficient exocrine pancreas progressively loses acinar cells. Acinar cells are tightly packed in wild-type (A, P20). In contrast, PKO acinar cells have become degranulated giving a light pink appearance to the cytoplasm in the PKO pancreas (B, P20). The same phenotype is seen in acinar cell-specific PERK knockout (C, P19, exPKO). (D) Enlarged views of dying oncotic cells seen in (B) and (C). Some cells have lost nuclear staining (upper arrow) while others retain nuclear staining (lower arrow) (E) At P19, this particular exPKO mouse has already lost most of the exocrine pancreas although typically this degree of atrophy is not seen until 3–4 months of age. Arrows indicate examples of the smaller number of acini remaining. (F) In older mice (P162), acinar cells have been replaced by other cell types including adipocytes. Only a few dark pink acini are seen. Islets (arrows) still maintain an apparent normal structure. The animal also showed a normal glucose clearance rate. Red arrow indicates a few remaining acini. (G) In some cases, mutant acinar cells dedifferentiate into duct-like structures (P31) with abnormally large centroacinar ducts (black arrows). In the beginning of this process, duct cells still contain zymogen granules (right panel, white arrow). In some of these duct-like structures the presumptive acinar cells have completely lost zymogen granules (right panel, white arrow). (H) Conditional deletion of the Perk gene in 3-month-old CreERT2; Perk flox/flox mice also results in the appearance of oncotic cells. Two oncotic acinar cells are enlarged (inset) with lower left still exhibiting nuclear staining while the cell in the upper right shows a nuclear ghost. H&E staining. A-C, H, 200x; E, 100x; F, 80x; D, G, 600x.