Abstract
Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1aCreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1afloxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.
Highlights
A great volume of study has identified key transcriptional factors that play central roles in cell specification, growth and differentiation during organogenesis
We found that Ptf1a deletion caused a shift in identity to duct cells and severe apoptosis in acinar cells, which resulted in a rapid reduction of pancreatic mass
We show that conditional Ptf1a loss in adult acinar cells causes endoplasmic reticulum (ER) stress and activates apoptosis pathways to decrease pancreatic size
Summary
A great volume of study has identified key transcriptional factors that play central roles in cell specification, growth and differentiation during organogenesis. Examples include the Yamanaka factors (Oct3/4, Sox[2], c-Myc and Klf4) for the creation of iPS cells[1,2], the induction of MyoD for the direct reprograming of fibroblasts to myoblasts[3], and the induction of Hnf4α and one of Foxa[1], Foxa[2] or Foxa[3] for the transdifferentiation to hepatic cells[4] These studies demonstrate the dosage of key transcription factors plays an important role in the regulation of cell behavior. Hoang et al reported that Ptf1a deletion in adult acinar cells promotes the expression of genes consistent with stomach lineage[11]. To explore the dosage effects of PTF1A on adult acinar cells, we used Elastase-CreERTM; Ptf1afloxed/floxed mice to inactivate PTF1A and tracked the fate of Ptf1a-deleted cells by lineage tracing analyses. We found evidence that the changes were associated with ER stress through activation of the PERK-eIF2α-ATF4 and ATF6 pathways and induction of the pro-apoptotic factor CHOP
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