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

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. Ptf1a^EDD 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 systemto pancreas,with formation of manyendocrine 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.