Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function.
Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (E)13.5, but defects in specification and differentiation were apparent at E15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.|Program in Developmental Biology, Vanderbilt University, Nashville, TN 37232.
Kathryn D
KD
Henley
Institute for Diabetes, Obesity and Metabolism and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia PA 19104.
Diana E
DE
Stanescu
Program in Developmental Biology, Vanderbilt University, Nashville, TN 37232.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232.
Peter A
PA
Kropp
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.|Program in Developmental Biology, Vanderbilt University, Nashville, TN 37232.
Christopher V E
CVE
Wright
Institute for Diabetes, Obesity and Metabolism and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Kyoung-Jae
KJ
Won
Institute for Diabetes, Obesity and Metabolism and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Doris A
DA
Stoffers
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.|Program in Developmental Biology, Vanderbilt University, Nashville, TN 37232.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232.|Department of Medicine, Vanderbilt University, Nashville, TN 37232.|Department of Veterans Affairs, Tennessee Valley Health Authority, Vanderbilt University, Nashville, TN 37212.
Maureen
M
Gannon
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014886:Weaning
D051792:Basic Helix-Loop-Helix Proteins; D005947:Glucose; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C407737:Neurog3 protein, mouse; C496606:Onecut1 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein