title: 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 pancreatic-commitment 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 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.
authors.affiliation: Program in Developmental Biology and Center for Stem Cell Biology, Nashville, TN 37232, USA Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Spencer G
authors.initials: SG
authors.lastname: Willet
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hale
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, Copenhagen N, DK-2200, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
authors.affiliation: Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacDonald
authors.affiliation: Program in Developmental Biology and Center for Stem Cell Biology, Nashville, TN 37232, USA Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA chris.wright@vanderbilt.edu.
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
mesh_terms: D000818:Animals; D004707:Endoderm / Q000196:embryology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D041981:Gastrointestinal Tract / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics; D006652:Histological Techniques; D051379:Mice; D018613:Microscopy, Confocal; D038081:Organogenesis / Q000235:genetics / Q000502:physiology*; D010179:Pancreas / Q000196:embryology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; C062602:transcription factor PTF1
keywords: Glandular stomach; Mouse; Pancreas; Pdx1; Ptf1a; Respecification