Abstract
BackgroundDeficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice.ResultsWe show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas.ConclusionWe conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.
Highlights
Deficiency of the PERK eukaryotic translation initiation factor 2α (eIF2α) kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues
PERK is cell-autonomously required in the exocrine pancreas We generated pancreatic acinar cell-specific Perk knockout mice by crossing a mouse carrying Cre recombinase driven by the Elastase-1 promoter ("Ela-Cre") [12] to a mouse carrying a floxed Perk gene [1]
Since 7–8% of the total pancreas is comprised of other cell types we estimate that 70% of acinar cells contained the deletion of Perk
Summary
Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. Abnormal signaling caused by various factors including hyper-stimulation with high doses of secretagogues can activate zymogens prematurely in the pancreas, which results in autodigestion of the cells and acute pancreatitis. We [1], and others [2] have independently showed that the lack of PERK (EIF2AK3) in mice results in atrophy of the exocrine pancreas This is consistent with earlier findings of pancreatic insufficiency in Wolcott-Rallison syndrome, a rare autosomal recessive disorder caused by a mutation in the human Perk gene [3,4]. These defects, which occur earlier in development, make it impossible to ascertain whether the anomalies occurring in the exocrine pancreas of PKO mice are cell-autonomous or secondary to dysfunctions in other organs
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