Dominant and context-specific control of endodermal organ allocation by Ptf1a

Abstract

The timing and gene regulatory logic of organ-fate commitment from within the posterior foregut of the mammalian endoderm is largely unexplored. Transient misexpression of a presumed pancreaticcommitment transcription factor, Ptf1a, in embryonic mouse endoderm (Ptf1a EDD ) dramatically expanded the pancreatic gene regulatory network within the foregut. Ptf1aEDD temporarily suppressed Sox2 broadly over the anterior endoderm. Pancreas-proximal organ territories underwent full tissue conversion. Early-stage Ptf1a EDD rapidly expanded the endogenous endodermal Pdx1-positive domain and recruited other pancreas-fate-instructive genes, thereby spatially enlarging the potential for pancreatic multipotency. Early Ptf1a EDD converted essentially the entire glandular stomach, rostral duodenum and extrahepatic biliary system to pancreas, with formation of many endocrine cell clusters of the type found in normal islets of Langerhans. Sliding the Ptf1a EDD expression window through embryogenesis revealed differential temporal competencies for stomach-pancreas respecification. The response to later-stage Ptf1a EDD changed radically towards unipotent, acinar-restricted conversion. We provide strong evidence, beyond previous Ptf1a inactivation or misexpression experiments in frog embryos, for spatiotemporally context-dependent activity of Ptf1a as a potent gain-of-function trigger of pro-pancreatic commitment.

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

“…The pancreas and stomach arise from nearby domains of the endoderm, and Ptf1a plays a key role in distinguishing the pancreas (12,13,25). Ectopic expression of Ptf1a in the anterior foregut endoderm at the onset of organogenesis is sufficient to redirect development of the prestomach domain to the pancreas (92)(93)(94). Our results show a complementary effect: inactivation of Ptf1a in pancreatic acinar cells releases a suppressed gastric gene expression program encompassing all gastric cell lineages.…”

Stomach development, stem cells and disease

“…Deletion of Hes1 in the mouse causes ectopic pancreas development in the stomach through activation of the TF gene Ptf1a (Fukuda et al, 2006) and forced expression of Ptf1a converts stomach tissue to pancreas (Jarikji et al, 2007;Willet et al, 2014). Therefore, Hes1-mediated Notch signaling and its control over Ptf1a are required for proper specification of these organs.…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…214 Additionally at an early stage, pancreas-proximal organ switch occurred producing all pancreatic lineages. 214 The endogenous endodermal Pdx1 C domain expanded and triggered other pancreatic progenitor genes. 214 Thus there is a developmental window during which the endoderm can be re-specified.…”

“…214 The endogenous endodermal Pdx1 C domain expanded and triggered other pancreatic progenitor genes. 214 Thus there is a developmental window during which the endoderm can be re-specified. 214 Nuclear receptor subfamily 5 group A member 2 (NR5A2) is a member of the nuclear hormone receptor family and has been identified as a regulator of pancreatic organogenesis.…”

“…214 Thus there is a developmental window during which the endoderm can be re-specified. 214 Nuclear receptor subfamily 5 group A member 2 (NR5A2) is a member of the nuclear hormone receptor family and has been identified as a regulator of pancreatic organogenesis. 215 NR5A2 is required for the expansion of the nascent pancreatic epithelium and subsequently in the genesis of MPCs.…”