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      Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function.

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          Abstract

          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.

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          Elsevier BV
          2211-1247
          June 21 2016
          : 15
          : 12
          Affiliations
          [1 ] Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.
          [2 ] Program in Developmental Biology, Vanderbilt University, Nashville, TN 37232.
          [3 ] Institute for Diabetes, Obesity and Metabolism and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
          [4 ] Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia PA 19104.
          [5 ] Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232.
          [6 ] Department of Medicine, Vanderbilt University, Nashville, TN 37232.
          [7 ] Department of Veterans Affairs, Tennessee Valley Health Authority, Vanderbilt University, Nashville, TN 37212.
          Article
          NIHMS788042 S2211-1247(16)30623-4
          10.1016/j.celrep.2016.05.040
          4917419
          27292642

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