title: A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells.
abstract: The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors.
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Hung Ping
authors.initials: HP
authors.lastname: Shih
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA; DanStem, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Seymour
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Nisha A
authors.initials: NA
authors.lastname: Patel
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Ruiyu
authors.initials: R
authors.lastname: Xie
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, 2213 Garland Avenue, Nashville, TN 37232, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: masander@ucsd.edu.
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D000818:Animals; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein